Diaryl Substituted Pyridinones

ABSTRACT

Disclosed are compounds Formula I  
                 
         and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5  are defined herein. These compounds are useful for treating diseases and conditions caused or exacerbated by unregulated p38 MAP Kinase and/or TNF activity. Pharmaceutical compositions containing the compounds, methods of preparing the compounds and methods of treatment using the compounds are also disclosed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The instant invention relates to substituted pyridinones that are usefulfor treating diseases and conditions caused or exacerbated byunregulated p38 MAP kinase activity. Pharmaceutical compositionscontaining the pyridinone compounds, methods of preparing the compoundsand methods of treatment using the compounds are also disclosed.

2. Description of the Related Art

Nearly all cell surface receptors use one or more of themitogen-activated protein kinase (MAP kinase) cascades during signaltransduction. MAP kinases are a family of proline-directedserine/threonine kinases that activate their substrates by dualphosphorylation. Four distinct subgroups of MAP kinases, p38 alpha, p38beta, p38 gamma, and p38 delta have been identified and each of theseconsists of a specific module of kinases that function downstream of. anactivating stimulus by phosphorylating and activating transcriptionfactors (e.g. ATF2, CHOP and MEF2C) as well as other kinases (e.g.MAPKAP-2 and MAPKAP-3). One subgroup of the MAP kinases is the p38 MAPkinase cascade, which is activated by a variety of signals includingproinflammatory cytokines such as tumor necrosis factor (TNF) andinterleukin-1 (IL-1) as well as bacterial lipopolysaccharides, andenvironmental stress (e.g., osmotic shock and ultraviolet radiation).Upon activation, the p38 cascade leads to the induction of geneexpression of several factors involved in inflammation and immunityincluding TNF, interleukin-6, granulocyte-macrophage colony stimulatingfactor (GM-CSF), and HIV long terminal repeat (Paul et al., CellSignal., 1997, 9, 403-410). The products of the p38 phosphorylationinhibit or modulate the production of inflammatory cytokines, includingTNF and IL-1, and cyclooxygenase-2, and also potentially block theeffects of these cytokines on their target cells, which thereforeinhibit or modulate inflammation.

p38 MAP kinases have also been shown to help prevent apoptosis duringischemia in cardiac myocytes, which suggests that p38 MAP kinaseinhibitors can be used for treating ischemic heart disease, p38 MAPkinase is also required for T-cell HIV-1 replication and may be a usefultarget for AIDS therapy. p38 Pathway inhibitors have also been used toincrease cancer cell sensitivity to cancer therapy.

TNF is a cytokine and a potent proinflammatory mediator implicated ininflammatory conditions such as arthritis, asthma, septic shock,non-insulin dependent diabetes mellitus, multiple sclerosis, asthma, andinflammatory bowel disease. TNF has also been implicated in viralinfections, such as HIV, influenza virus, and herpes virus includingherpes simplex virus type-1 (HSV-1), herpes simplex virus type-2(HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV),Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7(HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis,among others.

Excessive or unregulated TNF production has also been shown to produceelevated levels of IL-1. Inhibition of TNF, therefore, should reducelevels of IL-1 and ameliorate disease states caused by unregulated IL-1synthesis. Such disease states include rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis, gouty arthritis, sepsis, septic shock,endotoxic shock, gram negative sepsis, toxic shock syndrome, adultrespiratory distress syndrome, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcosis, bone resorptiondiseases, reperfusion injury, graft versus host reaction, alallograftrejections, fever and myalgias due to infection, cachexia secondary toinfection or malignancy, cachexia secondary to acquired immunedeficiency syndrome (AIDS), AIDS related complex (ARC), keloidformation, scar tissue formation, Crohn's disease, ulcerative colitis,and pyresis.

IL-1 has also been shown to mediate a variety of biological activitiessuch as the activation of T-helper cells, induction of fever,stimulation of prostaglandin or collagenase production, neutrophilchemotaxis, and the suppression of plasma iron levels (Rev. Infect.Disease, 6, 51 (1984)). Elevated levels of IL-1 have also beenimplicated in mediating or exacerbating a number of disease statesincluding rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis,gouty arthritis, inflammatory bowel disease, adult respiratory distresssyndrome (ARDS), psoriasis, Crohn's disease, ulcerative colitis,anaphylaxis, muscle degeneration, cachexia, Reiter's syndrome, type Iand type II diabetes, bone resorption diseases, ischemia reperfusioninjury, arteriosclerosis, brain trauma, multiple sclerosis, sepsis,septic shock, and toxic shock syndrome. Viruses sensitive to TNFinhibition, such as HIV-1, HIV-2, HIV-3, are also affected by IL-1production. In rheumatoid arthritis, both IL-1 and TNF inducecollagenase synthesis and ultimately lead to tissue destruction withinarthritic-joints (Lymphokine Cytokine Res. (11): 253-256, (1992) andClin. Exp. Immunol. 989:244-250, (1992)).

IL-6 is another pro-inflammatory cytokine, which is associated with manyconditions including inflammation.

Consequently, TNF, IL-1 and IL-6 affect a wide variety of cells andtissues and are important inflammatory mediators of a wide variety ofdisease states and conditions. The inhibition of these cytokines byinhibition or modulation of p38 kinase is of benefit in controlling,reducing and alleviating many of these disease states and conditions.Therefore, the present invention concerns finding small moleculeinhibitors or modulators of p38 kinase and the p38 kinase pathway.

SUMMARY OF THE INVENTION

In a broad aspect, the invention provides compounds of Formula I:

and pharmaceutically acceptable salts thereof, wherein R₁ is H, halogen,alkyl, carboxaldehyde, hydroxyalkyl, haloalkyl, arylalkoxy, arylalkyl,CN, alkanoyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl optionallysubstituted with trimethylsilyl, or arylalkanoyl,

-   -   wherein the aryl portion of arylalkoxy, arylalkyl, and        arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or        5 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄        alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂H;

wherein the alkyl portion of the alkyl, hydroxyalkyl, arylalkoxy,arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups isunsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, methoxy, ethoxy or spirocyclopropyl;

-   R₂ is H, arylalkoxy, arylalkyl, —SO₂CF₃, alkynyl, arylalkynyl,    aryloxy, —NR₆R₇, NR₆R₇alkyl, OH, halogen, arylthioalkoxy, alkoxy,    —OC(O)NH(CH₂)_(n)aryl, —OC(O)N(alkyl) (CH₂)_(n)aryl, alkyl,    alkoxyalkoxy, dialkylamino, heteroaryl, heterocycloalkyl,    hydroxyalkyl, haloalkyl, or CO₂H, wherein    -   n is 0, 1, 2, 3, 4, 5 or 6;    -   the aryl portion of arylalkoxy, aryloxy, arylthioalkoxy,        —OC(O)NH(CH₂)_(n)aryl, and —OC(O)N(alkyl) (CH₂)_(n)aryl or the        heteroaryl and heterocycloalkyl groups is unsubstituted or        substituted with 1, 2, 3, 4, or 5 groups that are independently        halogen, haloalkyl, heteroaryl, heteroarylalkyl, NR₆R₇,        NR₆R₇alkyl, —OC(O)NR₆R₇, wherein    -   R₆ and R₇ are independently at each occurrence H, alkyl, alkoxy,        alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl, wherein the        aryl portion of arylalkyl, arylalkoxy, or arylalkanoyl is        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy;-   R₃ is H, halogen, alkoxycarbonyl, arylalkoxycarbonyl,    aryloxycarbonyl, arylalkyl, hydroxyalkyl, haloalkyl,    —OC(O)NH(CH₂)_(n)aryl, aryloxy, arylthio, arylalkoxy, —OC(O)N(alkyl)    (CH₂)_(n)aryl, thioalkoxy, arylthioalkoxy, alkenyl, NR₆R₇ or alkyl,    wherein-   the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl,    —OC(O)NH(CH₂)_(n)aryl, arylalkoxy, —OC(O)N(alkyl) (CH₂)_(n)aryl, and    arylthioalkoxy, is unsubstituted or substituted with 1, 2, or 3    groups that are independently, halogen, alkoxy, alkyl, haloalkyl, or    haloalkoxy,    -   wherein n is 0, 1, 2, 3, 4, 5, or 6; or-   R₂, R₃ and the carbons to which they are attached form an aryl,    heterocycloalkyl or a heteroaryl ring, which is unsubstituted or    substituted with 1, 2, or 3 groups that are independently alkyl,    alkoxy, halogen, arylalkyl, arylalkoxy, heteroarylalkyl,    heterocycloalkylalkyl, CN, NO₂, haloalkyl, or haloalkoxy;-   R₄ is H, alkyl, arylalkoxy, arylalkyl, hydroxyalkyl, haloalkyl,    NR₆R₇alkyl, alkoxy, halogen, alkoxyalkyl, or alkoxyalkoxy, wherein    -   the aryl portion of arylalkoxy, and arylalkyl is unsubstituted        or substituted with 1, 2, 3, 4, or 5 groups that are        independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl,        or haloalkoxy; and-   R₅ is H, arylalkyl, halogen, alkyl, aryl, alkoxy,    heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl,    haloalkyl, heteroarylalkyl, heterocycloalkyl, or heteroaryl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl,        CO₂H, CN, amidinooxime, NR₆R₇, NR₆R₇alkyl, —C(O)NR₆R₇, amidino,        haloalkyl, or haloalkoxy.

The invention also includes the intermediates that are useful in makingthe compounds of the invention.

These compounds bind and/or interact with p38 kinase and/or TNF.Preferably, they inhibit the activity of p38 kinase and/or TNF. They aretherefore used in treating p38 map kinase or TNF mediated disorders.Preferably they are used in treating p38 alpha or TNF mediateddisorders.

The instant invention also includes pharmaceutical compositionscomprising at least one compound of formula I and at least onepharmaceutically acceptable carrier, solvent, adjuvant or excipient.

The instant invention also includes methods of treating a TNF mediateddisorder, a p38 kinase mediated disorder, inflammation and/or arthritisin a subject, the method comprising treating a subject having orsusceptible to such disorder or condition with atherapeutically-effective amount of a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

A preferred class of compounds of formula I are those wherein,

-   R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy,    arylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl, or arylalkanoyl,    -   wherein the aryl portion of arylalkoxy, arylalkyl, and        arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or        5 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄        alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂H;    -   wherein the alkyl portion of the alkyl, hydroxyalkyl,        arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and        arylalkanoyl groups is unsubstituted or substituted with 1, 2,        or 3 groups that are independently halogen, methoxy, ethoxy or        spirocyclopropyl;-   R₂ is arylalkoxy, aryloxy, OH, halogen, arylthioalkoxy, alkoxy,    —OC(O)NH(CH₂)_(n)aryl, —OC(O)N(alkyl) (CH₂),aryl, alkyl,    alkoxyalkoxy, dialkylamino, heteroaryl, heterocycloalkyl, or CO₂H,    wherein    -   n is 0, 1, 2, 3, 4, 5 or 6;    -   the aryl portion of arylalkoxy, aryloxy, arylthioalkoxy,        —OC(O)NH(CH₂)_(n)aryl, and —OC (O)N(alkyl) (CH₂)_(n)aryl or the        heteroaryl and heterocycloalkyl groups is unsubstituted or        substituted with 1, 2, 3, 4, or 5 groups that are independently        halogen, haloalkyl, heteroaryl, heteroarylalkyl, NR₆R₇,        NR₆R₇alkyl, —OC(O)NR₆R₇, wherein    -   R₆ and R₇ are independently at each occurrence H, alkyl, alkoxy,        alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl, wherein the        aryl portion of arylalkyl, arylalkoxy, or arylalkanoyl is        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy;-   R₃ is halogen, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl,    arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy, —OC(O)N(alkyl)    (CH₂)_(n)aryl, aryloxy, arylthio, thioalkoxy, arylthioalkoxy,    alkenyl, NR₆R₇ or alkyl, wherein the aryl portion of    arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl,    —OC(O)NH(CH₂)_(n)aryl, arylalkoxy, —OC(O)N(alkyl) (CH₂)_(n)aryl, and    arylthioalkoxy, is unsubstituted or substituted with 1, 2, or 3    groups that are independently, halogen, alkoxy, alkyl, haloalkyl, or    haloalkoxy,    -   wherein n is 0, 1, 2, 3, 4, 5, or 6; or-   R₂, R₃ and the carbons to which they are attached form an aryl,    heterocycloalkyl or a heteroaryl ring, which is unsubstituted or    substituted with 1, 2, or 3 groups that are independently alkyl,    alkoxy, halogen, arylalkyl, arylalkoxy, heteroarylalkyl,    heterocycloalkylalkyl, CN, NO₂, haloalkyl, or haloalkoxy;-   R₄ is H, alkyl, arylalkoxy, arylalkyl, hydroxyalkyl, haloalkyl,    NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the aryl    portion of arylalkoxy, arylalkyl is unsubstituted or substituted    with 1, 2, 3, 4, or 5 groups that are independently halogen,    hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and-   R₅ is arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl,    heteroarylalkyl, heterocycloalkyl, or heteroaryl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl,        CO₂H, CN, amidinooxime, NR₆R₇, NR₆R₇alkyl, —C(O)NR₆R₇, amidino,        haloalkyl, or haloalkoxy.

Another preferred class of compounds of formula I are those wherein:

-   R₁ is alkanoyl, halogen, arylalkanoyl, arylalkyl, alkoxyalkyl,    hydroxyalkyl, or carboxaldehyde, wherein    -   the aryl portion of arylalkyl, and arylalkanoyl is unsubstituted        or substituted with 1, 2, 3, 4, or 5 groups that are        independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN,        haloalkyl, haloalkoxy or CO₂H;    -   the alkyl portion of the hydroxyalkyl, arylalkyl, alkanoyl,        alkoxyalkyl and arylalkanoyl groups are unsubstituted or        substituted with 1, 2, or 3 groups that are independently        halogen, methoxy, ethoxy or spirocyclopropyl;-   R₂ is arylalkoxy, aryloxy, OH, halogen, arylthioalkoxy, alkoxy,    —OC(O)NH(CH₂)_(n)aryl, —OC(O)N(alkyl) (CH₂)_(n)aryl, alkyl,    alkoxyalkoxy, dialkylamino, pyridyl, pyrimidyl, pyridazyl,    pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl,    tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl,    triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl,    thiazolyl, thiophenyl, or CO₂H, wherein    -   n is 0, 1, 2, 3, 4, 5 or 6;-   the aryl portion of arylalkoxy, aryloxy, arylthioalkoxy,    —OC(O)NH(CH₂)_(n)aryl, and —OC(O)N(alkyl) (CH₂)_(n)aryl or the    heteroaryl and heterocycloalkyl groups is unsubstituted or    substituted with 1, 2, 3, 4, or 5 groups that are independently    halogen, haloalkyl, heteroaryl, heteroarylalkyl, NR₆R₇, NR₆R₇alkyl,    —OC(O)NR₆R₇, wherein    -   R₆ and R₇ are independently at each occurrence H, alkyl, alkoxy,        alkanoyl, arylalkyl,-arylalkoxy, or arylalkanoyl, wherein the        aryl portion of arylalkyl, arylalkoxy, or arylalkanoyl is        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy;-   R₃ is halogen, arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl,    —OC(O)NH(CH₂)_(n)aryl, arylalkoxy, —OC(O)N(alkyl) (CH₂)_(n)aryl,    aryloxy, arylthio, thioalkoxy, arylthioalkoxy, or alkenyl, NR₆R,₇ or    alkyl, wherein    -   the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl,        arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy, —OC(O)N(alkyl)        (CH₂)_(n)aryl, and arylthioalkoxy, is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy,    -   wherein n is 0, 1, 2, 3, 4, 5, or 6; or-   R₂, R₃ and the carbons to which they are attached form an aryl,    heterocycloalkyl or a heteroaryl ring, which is unsubstituted or    substituted with 1, 2, or 3 groups that are independently alkyl,    alkoxy, halogen, arylalkyl, arylalkoxy, heteroarylalkyl,    heterocycloalkylalkyl, CN, NO₂, haloalkyl, or haloalkoxy;-   R₄ is H, alkyl, arylalkoxy, arylalkyl, hydroxyalkyl, haloalkyl,    NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the aryl    portion of arylalkoxy, arylalkyl is unsubstituted or substituted    with 1, 2, 3, 4, or 5 groups that are independently halogen,    hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and-   R₅ is arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl,    heteroarylalkyl, arylthioalkyl, heterocycloalkyl, or heteroaryl,    wherein-   each of the above is unsubstituted or substituted with 1, 2, 3, 4,    or 5 groups that are independently alkyl, halogen, alkoxy,    arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, CO₂H,    CN, amidinooxime, NR₆R₇, NR₆R₇alkyl, —C(O)NR₆R₇, amidino, haloalkyl,    or haloalkoxy.

A more preferred class of compound are those wherein

-   R₂ is arylalkoxy, aryloxy, OH, halogen, arylthioalkoxy, alkoxy,    alkyl, alkoxyalkoxy, —OC(O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl)    (CH₂)_(n)phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazolyl,    imidazolyl, pyrrolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,    tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl,    piperidinyl, hexahydropyrimidinyl, or thiazolyl, thiophenyl, wherein    -   n is 0, 1, 2, 3, 4, S or 6; and        the above are unsubstituted or substituted with 1, 2, 3, 4, or 5        groups that are independently halogen, haloalkyl, or thiophenyl.

Another more preferred class of compound are those wherein

-   R₅ is phenyl(C₁-C₆)alkyl, (C₁-C₆)alkyl, phenyl, naphthyl,    (C₁-C₆)alkoxy, piperidinyl(C₁-C₆)alkyl, pyrrolyl(C₁-C₆)alkyl,    pyrrolidinyl(C₁-C₆)alkyl, imidazolidinyl(C₁-C₆)alkyl,    pyrazolyl(C₁-C₆)alkyl, imidazolyl(C₁-C₆)alkyl,    tetrahydropyridinyl(C₁-C₆)alkyl, thiophenyl(C₁-C₆)alkyl, arylthio    (C₁-C₆)alkyl, pyridyl, or pyridyl(C₁-C₆)alkyl, wherein each of the    above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups    that are independently (C₁-C₄)alkyl, fluoro, chloro, bromo,    (C₁-C₄)alkoxy, phenyl(C₁-C₄)alkoxy, thio(C₁-C₄)alkoxy,    (C₁-C₄)alkoxycarbonyl, phenyl(C₁-C₄)alkoxycarbonyl, CO₂H, CN,    amidinooxime, NR₆R₇, NR₆R₇alkyl, —C(O)NR₆R₇, amidino, CF₃, —CF₂CF₃,    OCF₃ or OCF₂CF₃.

Yet another more preferred class of compound are those wherein

-   R₁ is halogen, (C₁-C₆)alkanoyl, phenyl(C₁-C₆)alkanoyl,    naphthyl(C₁-C₆)alkanoyl, naphthyl(C₁-C₆)alkyl, phenyl(C₁-C₆)alkyl,    alkoxyalkyl, hydroxyalkyl, or carboxaldehyde, wherein    -   the phenyl and napthyl portions of the above are unsubstituted        or substituted with 1, 2, 3, 4, or 5 groups that are        independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN,        CF₃, OCF₃ or CO₂H;    -   the alkyl portion of the hydroxyalkyl, arylalkyl, alkanoyl,        alkoxyalkyl and arylalkanoyl groups are unsubstituted or        substituted with 1, 2, or 3 groups that are independently        halogen, methoxy, or ethoxy.

Yet another more preferred class of compound are those wherein

-   R₃ is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl,    phenyl(C₁-C₆)alkyl, —OC(O)NH(CH₂)_(n)aryl, phenylalkoxy,    —OC(O)N(alkyl) (CH₂)_(n)aryl, phenyloxy, naphthyloxy, phenylthio,    thioalkoxy, arylthioalkoxy, (C₂-C₆)alkenyl, NR₆R₇ or alkyl, wherein    -   the phenyl, naphthyl, and aryl portions of arylalkoxycarbonyl,        aryloxycarbonyl, arylalkyl, —OC(O)NH (CH₂)_(n)aryl,        arylthioalkoxy, arylalkoxy, and—OC(O)N(alkyl) (CH₂)_(n)aryl, are        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, alkoxy, alkyl, CF₃, or OCF₃; and    -   wherein n is 0, 1, 2, 3, 4, 5, or 6.

Still yet another more preferred class of compound are those wherein

-   R₄ is H, (C₁-C₆)alkyl, phenylalkoxy, phenyl(C₁-C₆)alkyl,    hydroxyalkyl, haloalkyl, NR₆R₇alkyl, (C₁-C₆)alkoxy, alkoxyalkyl, or    alkoxyalkoxy, wherein    -   the phenyl portion of the above groups is unsubstituted or        substituted with 1, 2, 3, 4, or 5 groups that are independently        halogen, hydroxy, alkoxy, alkyl, nitro, CF₃, or OCF₃.

Still yet another more preferred class of compound are those wherein

-   R₁ is halogen, (C₁-C₆)alkanoyl, phenyl(C₁-C₆)alkanoyl,    naphthyl(C₁-C₆)alkanoyl, naphthyl(C₁-C₆)alkyl, phenyl(C₁-C₆)alkyl,    alkoxyalkyl, hydroxyalkyl, or carboxaldehyde, wherein    -   the phenyl and napthyl portions of the above are unsubstituted        or substituted with 1, 2, 3, 4, or 5 groups that are        independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN,        CF₃, OCF₃ or CO₂H;    -   the alkyl portion of the above groups are unsubstituted or        substituted with 1, 2, or 3 groups that are independently        halogen, methoxy, or ethoxy.-   R₂ is phenylalkoxy, aryloxy, OH, halogen, phenylthioalkoxy, alkoxy,    alkyl, alkoxyalkoxy, —OC(O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl)    (CH₂)_(n)phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, or    thiophenyl, wherein    -   n is 0/ 1, 2, 3, or 4, and    -   the above groups are unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen, halo(C₁-C₄)alkyl,        thiophenyl; R₃ is halogen, phenylalkoxycarbonyl,        phenyloxycarbonyl, phenyl(C₁-C₆)alkyl, phenylalkoxy, phenyloxy,        phenylthio, thioalkoxy, arylthioalkoxy, (C₂-C₅)alkenyl, NR₆R₇ or        alkyl, wherein    -   the phenyl, naphthyl, and aryl portions of arylalkoxycarbonyl,        aryloxycarbonyl, arylalkyl, —OC(O)NH(CH₂)_(n)aryl,        arylthioalkoxy, arylalkoxy, and —OC(O)N(alkyl)(CH₂)_(n)aryl, are        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, alkoxy, alkyl, CF₃, or OCF₃,        wherein n is 0, 1, 2, 3, 4, 5, or 6; or-   R₄ is H, (C₁-C₆)alkyl, phenylalkoxy, phenyl(C₁-C₆)alkyl,    hydroxyalkyl, haloalkyl, alkoxyalkyl, or alkoxyalkoxy, wherein    -   the phenyl portion of the above groups are unsubstituted or        substituted with 1, 2, 3, 4, or. 5 groups that are independently        halogen, hydroxy, alkoxy, alkyl, nitro, CF₃, or OCF₃.-   R₅ is phenyl(C₁-C₆)alkyl, (C₁-C₆)alkyl, phenyl, naphthyl, pyridyl,    (C₁-C₆alkoxy, piperidinyl(C₁-C₆alkyl, pyrrolyl(C₁-C₆alkyl,    imidazolidinyl(C₁-C₆)alkyl, pyrazolyl(C₁-C₆ )alkyl,    imidazolyl(C₁-C₆)alkyl, tetrahydropyridinyl(C₁-C₆)alkyl,    thiophenyl(C₁-C₆)alkyl, phenylthio (C₁-C₆)alkyl, or    pyridyl(C₁-C₆)alkyl, wherein each of the above is unsubstituted or    substituted with 1, 2, or 3 groups that are independently    (C₁-C₄)alkyl, fluoro, chloro, bromo, (C₁-C₄)alkoxy,    phenyl(C₁-C₄)alkoxy, thio(C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl,    phenyl(C₁-C₄)alkoxycarbonyl, CO₂H, CN, amidinooxime, NR₆R₇,    NR₆R₇alkyl, —C(O)NR₆R₇, amidino, CF₃, —CF₂CF₃, OCF₃ or OCF₂CF₃.

An even more preferred class of compounds is those compounds wherein

-   R₁ is halogen, (C₁-C₄)alkanoyl, phenyl(C₁-C₄)alkanoyl, benzyl,    phenethyl, phenpropyl, hydroxyalkyl, or carboxaldehyde, wherein    -   the above phenyl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently halogen, C₁-C₄ alkyl,        C₁-C₄ alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H;    -   the alkyl portion of the above groups are unsubstituted or        substituted with 1, 2, or 3 groups that are independently        halogen, methoxy, or ethoxy;-   R₂ is benzyloxy, phenethyloxy, phenpropyloxy, phenbutyloxy,    phenyloxy, OH, halogen, phenylthioalkoxy, alkoxy, alkyl,    alkoxyalkoxy, wherein    -   n is 0, 1, 2, 3, or 4, and    -   the above groups are unsubstituted or substituted with 1, 2, or        3, groups that are independently halogen, halo(C₁-C₄)alkyl, or        thiophenyl;-   R₃ is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl,    phenyl(C₁-C₆)alkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy,    phenylthioalkoxy, (C₂-C₆)alkenyl, NR₆R₇ or alkyl, wherein    -   the above phenyl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently, halogen, alkoxy,        (C₁-C₄)alkyl, CF₃, or OCF₃,-   R₄ is H, (C₁-C₆)alkyl, phenylalkoxy, benzyl, phenethyl,    hydroxyalkyl, haloalkyl, alkoxyalkyl, or alkoxyalkoxy, wherein    -   the phenyl portion of the above groups are unsubstituted or        substituted with 1, 2, or 3 groups that are independently        halogen, hydroxy, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, nitro, CF₃, or        OCF₃.-   R₅ is benzyl, phenethyl, phenpropyl, phenbutyl, (C₁-C₆)alkyl,    phenyl, or pyridyl, wherein each of the above is unsubstituted or    substituted with 1, 2, or 3 groups that are independently    (C₁-C₄)alkyl, fluoro, chloro, bromo, (C₁-C₄)alkoxy,    phenyl(C₁-C₄)alkoxy, thio(C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, CO₂H,    CN, amidinooxime, NR₆R₇, amidino, CF₃, or OCF₃.

Still yet, an even more preferred class of compounds is those compoundswherein

-   R₁ is bromo, phenyl(C₁-C₄)alkanoyl, benzyl, phenethyl, phenpropyl,    hydroxyalkyl, or CHO, wherein    -   the above phenyl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently halogen, C₁-C₄ alkyl,        C₁-C₄ alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H;-   R₂ is benzyloxy, phenethyloxy, phenpropyloxy, phenbutyloxy,    phenyloxy, OH, halogen, ro phenylthioalkoxy, wherein    -   n is 0, 1, 2, 3, or 4, and    -   the above groups are unsubstituted or substituted with 1, 2, or        3, groups that are independently halogen, halo(C₁-C₄)alkyl, or        thiophenyl;-   R₃ is bromo, phenylalkoxycarbonyl, phenyloxycarbonyl, benzyl,    phenethyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy,    phenylthioalkoxy, (C₂-C₆)alkenyl, NR₆R₇ or alkyl, wherein the above    phenyl groups are unsubstituted or substituted with 1, 2, or 3    groups that are independently, halogen, is alkoxy, (C₁-C₄)alkyl,    CF₃, or OCF₃,-   R₄ is H, (C₁-C₆)alkyl, phenylalkoxy, benzyl, or phenethyl, wherein    the phenyl portion of the above groups are unsubstituted or    substituted with 1, 2, or 3 groups that are independently halogen,    hydroxy, (C₁-C₄)alkoxy, (C₁-C₄) alkyl, nitro, CF₃, or OCF₃.-   R₅ is benzyl, phenethyl, phenpropyl, (C₁-C₆)alkyl, phenyl, or    pyridyl, wherein each of the above is unsubstituted or substituted    with 1, 2, or 3 groups that are independently (C₁-C₄)alkyl, fluoro,    chloro, bromo, (C₁-C₄)alkoxy, CO₂H, CN, amidinooxime, amidino, CF₃,    or OCF₃.

Another embodiment of the invention is those compounds of formula IIIwherein

-   R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy,    arylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl, or arylalkanoyl,    -   wherein the aryl portion of arylalkoxy, arylalkyl, and        arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or        5 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄        alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂H;    -   wherein the alkyl portion of the alkyl, hydroxyalkyl,        arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and        arylalkanoyl groups is unsubstituted or substituted with 1, 2,        or 3 groups that are independently halogen, methoxy, ethoxy or        spirocyclopropyl;-   R₂ is H, arylthio, —OC(O)NH(CH₂)_(n)aryl, arylalkyl, —OC(O)N(alkyl)    (CH₂)_(n)aryl, or arylthioalkoxy, wherein n is 1, 2, 3, 4, or 5;-   R₃ is halogen, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl,    arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy, —OC(O)N(alkyl)    (CH₂)_(n)aryl, aryloxy, arylthio, thioalkoxy, arylthioalkoxy,    alkenyl, NR₆R₇ or alkyl, wherein    -   the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl,        arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy, —OC(O)N(alkyl)        (CH₂)_(n)aryl, and arylthioalkoxy, is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy,    -   wherein n is 0, 1, 2, 3, 4, 5, or 6; or-   R₄ is H, alkyl, arylalkoxy, arylalkyl, hydroxyalkyl, haloalkyl,    NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein    -   The aryl portion of arylalkoxy, arylalkyl is unsubstituted or        substituted with 1, 2, 3, 4, or 5 groups that are independently        halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or        haloalkoxy; and-   R₅ is arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl,    heteroarylalkyl, arylthioalkyl, heterocycloalkyl, or heteroaryl,    wherein each of the above is unsubstituted or substituted with 1, 2,    3, 4, or 5 groups that are independently alkyl, halogen, alkoxy,    arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, CO₂H,    CN, amidinooxime, NR₆R₇, NR₆R₇alkyl, —C(O)NR₆R₇, amidino, haloalkyl,    or haloalkoxy.

More preferred compounds of formula III are those wherein

-   R₁ is H, F, Cl, Br, (C₁-C₆)alkyl, carboxaldehyde,    hydroxy(C₁-C₆)alkyl, phenyl(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkyl, CN, or    phenyl(C₁-C₆)alkanoyl    -   wherein the phenyl portion of the above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently        halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN, haloalkyl,        haloalkoxy or CO₂H;    -   wherein the alkyl portion of above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently        halogen, methoxy, or ethoxy.

Other more preferred compounds of formula III are those wherein

-   R₂ is H, phenylthio, —OC (O)NH(CH₂)_(n)aryl, phenylalkyl,    —OC(O)N(alkyl) (CH₂)_(n)aryl, or phenylthio(C₁-C₆)alkoxy, wherein    -   n is 1, 2, 31 or 4.

Still other more preferred compounds of formula III are those wherein

-   R₃ is halogen, alkoxycarbonyl, phenylalkoxycarbonyl,    phenyloxycarbonyl, phenylalkyl, —OC(O)NH(CH₂)_(n)phenyl ,    phenylalkoxy, —OC(O)N(alkyl) (CH₂)_(n)phenyl, phenyloxy, phenylthio,    thioalkoxy, phenylthioalkoxy, alkenyl, NR₆R₇ or alkyl, wherein    -   the phenyl portion of the above is unsubstituted or substituted        with 1, 2, or 3 groups that are independently, halogen,        (C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo (C₁-C₄)alkyl, or halo        (C₁-C₄)alkoxy, wherein n is 0, 1, 2, 3, or 4.

Still other more preferred compounds of formula III are those wherein

-   R₄ is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl,    NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein    -   the phenyl portion of phenylalkoxy, phenylalkyl is unsubstituted        or substituted with 1, 2, or 3 groups that are independently        halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or        haloalkoxy.

Still other more preferred compounds of formula III are those wherein

-   R₅ is benzyl, phenethyl, phenpropyl, phenbutyl, alkyl, phenyl,    alkoxy, pyridyl(C₁-C₆)alkyl, phenyl(C₁-C₆) thioalkyl, pyrrolyl,    pyrrolyl(C₁-C₆)alkyl, or pyridyl, wherein each of the above is    unsubstituted or substituted with 1, 2, or 3 groups that are    independently (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy,    phenyl(C₁-C₆)alkoxy, (C₁-C₆) thioalkoxy, alkoxycarbonyl, CO₂H, CN,    amidinooxime, amidino, CF₃, or OCF₃.

Still other more preferred compounds of formula III are those wherein

-   R₁ is H, Br, (C₁-C₆)alkyl, carboxaldehyde, hydroxy(C₁-C₆)alkyl,    -   wherein the alkyl portion of above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently        halogen, methoxy, or ethoxy-   R₂ is H, phenylthio, —OC(O)NH(CH₂)_(n)aryl, phenylalkyl,    —OC(O)N(alkyl) (CH₂)_(n)aryl, or phenylthio(C₁-C₆)alkoxy, wherein    -   n is 1, 2, 3, or 4-   R₃ is bromo, alkoxycarbonyl, phenylalkoxycarbonyl,    phenyloxycarbonyl, benzyl, phenethyl, phenylalkoxy, phenyloxy,    phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR₆R₇ or alkyl,    wherein    -   the phenyl portion of the above is unsubstituted or substituted        with 1, 2, or 3 groups that are independently, halogen,        (C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, or halo(C₁-C₄        )alkoxy,    -   wherein n is 0, 1, 2, 3, or 4;-   R₄ is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl,    NR₆R₇alkyl, alkoxy, alkoxyalkyl, or wherein    -   the phenyl portion of phenylalkoxy, phenylalkyl is unsubstituted        or substituted with 1, 2, or 3 groups that are independently        halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy-   R₅ is benzyl, phenethyl, phenpropyl, phenbutyl, alkyl, phenyl,    phenyl(C₁-C₆)thioalkyl, pyrrolyl, or pyridyl, wherein each of the    above is unsubstituted or substituted with 1, 2, or 3 groups that    are independently (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, benzyloxy,    (C₁-C₆)thioalkoxy, alkoxycarbonyl, CO₂H, CN, amidinooxime, amidino,    CF₃, or OCF₃.

Another embodiment of the invention is those compounds of formula IV,wherein

-   R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy,    arylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl, or arylalkanoyl,    -   wherein the aryl portion of arylalkoxy, arylalkyl, and        arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or        5 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄        alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂H;    -   wherein the alkyl portion of the alkyl, hydroxyalkyl,        arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and        arylalkanoyl groups is unsubstituted or substituted with 1, 2,        or 3 groups that are independently halogen, methoxy, ethoxy or        spirocyclopropyl;-   R₂ is arylalkoxy, aryloxy, OH, halogen, arylthioalkoxy, alkoxy,    —OC(O)NH (CH₂)_(n)aryl, —OC(O)N(alkyl) (CH₂)_(n)aryl, alkyl,    alkoxyalkoxy, dialkylamino, or CO₂H, wherein    -   n is 0, 1, 2, 3, 4, 5 or 6;    -   the aryl portion of arylalkoxy, aryloxy, arylthioalkoxy,        —OC(O)NH(CH₂)_(n)aryl, and —OC(O)N(alkyl) (CH₂)_(n)aryl or the        heteroaryl and heterocycloalkyl groups is unsubstituted or        substituted with 1, 2, 3, 4, or 5 groups that are independently        halogen, haloalkyl, heteroaryl, heteroarylalkyl, NR₆R₇,        NR₆R₇alkyl, —OC(O)NR₆R₇, wherein    -   R₆ and R₇ are independently at each occurrence H, alkyl, alkoxy,        alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl, wherein the        aryl portion of arylalkyl, arylalkoxy, or arylalkanoyl is        unsubstituted or substituted with 1 , 2, or 3 groups that are        independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy;-   R₃ is halogen, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl,    arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy, —OC(O)N(alkyl)    (CH₂)_(n)aryl, aryloxy, arylthio, thioalkoxy, arylthioalkoxy,    alkenyl, NR₆R₇ or alkyl, wherein    -   the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl,        arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy, —OC(O)N(alkyl)        (CH₂)_(n)aryl, and arylthioalkoxy, is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy,    -   wherein n is 0, 1, 2, 3, 4, 5, or 6; or-   R₂, R₃ and the carbons to which they are attached form an aryl,    heterocycloalkyl or a heteroaryl ring, which is unsubstituted or    substituted with 1, 2, or 3 groups that are independently alkyl,    alkoxy, halogen, arylalkyl, arylalkoxy, heteroarylalkyl,    heterocycloalkylalkyl, CN, NO₂, haloalkyl, or haloalkoxy;-   R₄ is H, alkyl, arylalkoxy, arylalkyl, hydroxyalkyl, haloalkyl,    NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the aryl    portion of arylalkoxy, arylalkyl is unsubstituted or substituted    with 1, 2, 3, 4, or 5 groups that are independently halogen,    hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and-   R₅ is aryl, heterocycloalkylalkyl, heteroarylalkyl, arylthioalkyl,    heterocycloalkyl, or heteroaryl, wherein each of the above is    unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are    independently alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy,    alkoxycarbonyl, arylalkoxycarbonyl, CO₂H, CN, amidinooxime, NR₆R₇,    NR₆R₇alkyl, —C(O)NR₆R₇, amidino, haloalkyl, or haloalkoxy.

More preferred compounds of formula IV are those wherein

-   R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, phenylalkoxy,    phenylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl, or phenylalkanoyl,    -   wherein the above phenyl groups are unsubstituted or substituted        with 1, 2, 3, 4, or 5 groups that are independently halogen,        C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN, haloalkyl, haloalkoxy or        CO₂H;    -   wherein the alkyl portion of the alkyl, hydroxyalkyl,        arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and        arylalkanoyl groups is unsubstituted or substituted with 1, 2,        or 3 groups that are independently halogen, methoxy, ethoxy or        spirocyclopropyl;-   R₂ is phenylalkoxy, phenyloxy, OH, halogen, phenylthioalkoxy,    alkoxy, —OC(O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl) (CH₂)_(n)phenyl,    alkyl, alkoxyalkoxy, dialkylamino, or CO₂H, wherein    -   n is 0, 1, 2, 3, 4, 5 or 6;    -   the above aryl groups are unsubstituted or substituted with 1,        2, 3, 4, or 5 groups that are independently halogen, haloalkyl,        pyridyl, thiophenyl, NR₆R₇, NR₆R₇alkyl, or —OC(O)NR₆R₇, wherein    -   R₆ and R₇ are independently at each occurrence H, alkyl, alkoxy,        alkanoyl, phenylalkyl, phenylalkoxy, or phenylalkanoyl, wherein        the phenyl portion of the above is unsubstituted or substituted        with 1, 2, or 3 groups that are independently, halogen, alkoxy,        alkyl, haloalkyl, or haloalkoxy.

Other preferred compounds of formula IV are those wherein

-   R₃ is halogen, alkoxycarbonyl, phenylalkoxycarbonyl,    phenyloxycarbonyl, phenylalkyl, —OC(O)NH(CH₂)_(n)phenyl,    phenylalkoxy, —OC(O)N(alkyl) (CH₂)_(n)phenyl, phenyloxy, phenylthio,    thioalkoxy, phenylthioalkoxy, alkenyl, NR₆R₇ or alkyl, wherein    -   the phenyl portion of the above is unsubstituted or substituted        with 1, 2, or 3 groups that are independently, halogen, alkoxy,        alkyl, haloalkyl, or haloalkoxy,    -   wherein n is 0, 1, 2, 3, 4, 5, or 6; or-   R₂, R₃ and the carbons to which they are attached form an phenyl,    piperidinyl, pyrrolyl, pyrrolinyl or a pyridyl ring, each of which    is unsubstituted or substituted with 1, 2, or 3 groups that are    independently alkyl, alkoxy, halogen, phenylalkyl, phenylalkoxy, CN,    NO₂, haloalkyl, or haloalkoxy;-   R₄ is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl,    NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein    -   the phenyl portion of the above is unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen, hydroxy,        alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and-   R₅ is phenyl, naphthyl, pyrrolylalkyl, piperidinylalkyl    pyridinylalkyl, pyrimidinylalkyl, phenylthioalkyl, pyrrolyl,    piperidinyl, pyridyl, or thiophenylalkyl, wherein each of the above    is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that    are independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy,    alkoxycarbonyl, phenylalkoxycarbonyl, CO₂H, CN, amidinooxime,    NR₆R_(7,) NR₆R₇alkyl, —C(O)NR₆R₇, amidino, haloalkyl, or haloalkoxy.

Other preferred compounds of formula IV are those wherein

-   R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, benzyloxy,    phenethyloxy, phenpropyloxy, benzyl, phenethyl, phenpropyl, CN,    alkanoyl, alkoxy, or phenylC(O)—, phenylCH₂C(O)—, or    phenylCH₂CH₂C(O),    -   wherein the above phenyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen, C₁-C₄        alkyl, C₁-C₄ alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H;    -   wherein the above alkyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen, methoxy,        or ethoxy;-   R₂ is benzyloxy, phenethyloxy, phenpropyloxy, phenyloxy, OH,    halogen, phenylthioalkoxy, alkyl, alkoxy, —OC(O)NH(CH₂)_(n)phenyl,    —OC(O)N(alkyl) (CH₂)_(n)phenyl, dialkylamino, or CO₂H, wherein    -   n is 0, 1, 2, 3, or 4;

1the above aryl groups are unsubstituted or substituted with 1, 2, 3, 4,or 5 groups that are independently halogen, CF₃, pyridyl, thiophenyl,NR₆R₇, or NR₆R₇alkyl, wherein

-   -   R₆ and R₇ are independently at each occurrence H, alkyl,        alkanoyl, benzyl, or phenylC(O)—, wherein the phenyl portion of        the above is unsubstituted or substituted with 1, 2, or 3 groups        that are independently, halogen, alkoxy, alkyl, CF₃, or OCF₃;

-   R₃ is halogen, alkoxycarbonyl, phenylalkoxycarbonyl,    phenyloxycarbonyl, phenylalkyl, —OC(O)NH(CH₂)_(n)phenyl,    phenylalkoxy, —OC(O)N(alkyl) (CH2)_(n)phenyl, phenyloxy, phenylthio,    thioalkoxy, phenylthioalkoxy, alkenyl, NR₆R₇ or alkyl, wherein    -   the phenyl portion of the above is unsubstituted or substituted        with 1, 2, or 3 groups that are independently, halogen, alkoxy,        alkyl, haloalkyl, or haloalkoxy,    -   wherein n is 0, 1, 2, 3,or 4;

-   R₄ is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl,    NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein    -   the phenyl portion of the above is unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen, hydroxy,        alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and

-   R₅ is phenyl, naphthyl, pyrrolylalkyl, piperidinylalkyl    pyridinylalkyl, pyrimidinylalkyl, phenylthioalkyl, pyrrolyl,    piperidinyl, pyridyl, or thiophenylalkyl, wherein each of the above    is unsubstituted or substituted with 1, 2, or 3 groups that are    independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy,    alkoxycarbonyl, phenylalkoxycarbonyl, CO₂H, CN, amidinooxime, NR₆R₇,    NR₆R₇alkyl, —C(O)NR₆R₇, amidino, haloalkyl, or haloalkoxy.

Even more preferred compound of formula IV are those wherein

-   R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, benzyloxy,    phenethyloxy, benzyl, phenethyl, CN, (C₁-C₆)alkanoyl, alkoxy, or    phenylC(O)—, or phenylCH₂C(O)—,    -   wherein the above phenyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that, are independently halogen, C₁-C₄        alkyl, C₁-C₄ alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H;-   R₂ is benzyloxy, phenethyloxy, phenpropyloxy, phenyloxy, OH,    halogen, phenyl(C₁-C₄)thioalkoxy, —OC(O)NH(CH₂)_(n)phenyl,    —OC(O)N(alkyl) (CH₂)_(n)phenyl, or dialkylamino, wherein    -   n is 0, 1, 2, 3, or 4;    -   the above aryl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently halogen, CF₃, NR₆R,₇ or        NR₆R₇alkyl, wherein        -   R₆ and R₇ are independently at each occurrence H,            (C₁-C₆)alkyl, acetyl, benzyl, or phenylC(O)p13 , wherein the            phenyl portion of the above is unsubstituted or substituted            with 1, 2, or 3 groups that are independently, halogen,            alkoxy, alkyl, CF₃, or OCF₃;-   R₃ is halogen, alkoxycarbonyl, phenylalkoxycarbonyl,    phenyloxycarbonyl, phenylalkyl, phenylalkoxy, phenyloxy, phenylthio,    thioalkoxy, phenylthioalkoxy, alkenyl, NR₆R₇ or alkyl, wherein    -   the phenyl portion of the above is unsubstituted or substituted        with 1, 2, or 3 groups that are independently, halogen, alkoxy,        alkyl, haloalkyl, or haloalkoxy,        -   wherein n is 0, 1, 2, 3,or 4;-   R₄ is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl,    NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein    -   the phenyl portion of the above is unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen, hydroxy,        alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and-   R₅ is phenyl, phenyl(C₁-C₄)thioalkyl, pyridyl, or    thiophenyl(C₁-C₄)alkyl, wherein each of the above is unsubstituted    or substituted with 1, 2, or 3 groups that are independently    (C₁-C₄)alkyl, fluoro, chloro, bromo, (C₁-C₄)alkoxy, CN,    amidinooxime, amidino, CF₃, or OCF₃.

Still more preferred are those compounds wherein

-   R₅ is substituted with at least one group selected from fluoro,    chloro, bromo, and methyl.

The invention also includes a pharmaceutical composition comprising atleast one pharmaceutically acceptable carrier, solvent, adjuvant orexcipient and a compound according to Formula I.

Another preferred class of compounds of formula I are those of formulaX:

or a pharmaceutically acceptable salt thereof, wherein

-   R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy,    arylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, alkenyl,    alkynyl, arylalkynyl, or arylalkanoyl,    -   wherein the aryl portion of arylalkoxy, arylalkyl, and        arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or        5 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄        alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂H;    -   wherein the alkyl portion of the alkyl, hydroxyalkyl,        arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and        arylalkanoyl groups is unsubstituted or substituted with 1, 2,        or 3 groups that are independently halogen, methoxy, ethoxy or        spirocyclopropyl;-   R₂ is arylalkoxy, aryloxy, arylthioalkoxy, alkoxy,    —OC(O)NH(CH₂)_(n)aryl, —OC(O)N(alkyl) (CH₂)_(n)aryl, alkyl,    alkoxyalkoxy, dialkylamino, pyridyl, pyrimidyl, pyridazyl,    pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl,    tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl,    triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl,    thiazolyl, thiophenyl, or CO₂H, wherein    -   n is 0, 1, 2, 3, 4, 5 or 6;    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen, NR₆R₇, haloalkyl,        haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, NR₆R₇alkyl,        —OC(O)NR₆R₇, wherein    -   R₆ and R₇ are independently at each occurrence H, alkyl, alkoxy,        alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl, wherein the        aryl portion of arylalkyl, arylalkoxy, or arylalkanoyl is        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy;-   R₄ is H, alkyl, arylalkoxy, arylalkyl, hydroxyalkyl, haloalkyl,    NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the aryl    portion of. arylalkoxy, arylalkyl is unsubstituted or substituted    with 1, 2, 3, 4, or 5 groups that are independently halogen,    hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and-   R₅ is arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl,    heteroarylalkyl, heterocycloalkyl, or heteroaryl, wherein each of    the above is unsubstituted or substituted with 1, 2, 3, 4, or 5    groups that are independently alkyl, halogen, alkoxy, arylalkoxy,    thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, CO₂H, CN,    amidinooxime, NR₈R₉, NR₆R₇alkyl, —C(O)NR₆R₇, amidino, haloalkyl, or    haloalkoxy;    -   -   wherein R₈ is hydrogen, alkyl, alkanoyl, arylalkyl and            arylalkanoyl;        -   wherein R₉ is alkyl, alkanoyl, arylalkyl and arylalkanoyl;            provided that when R₂ is benzyloxy, and R₅ is benzyl or            methyl, R₁ is not hydrogen.

More preferred compounds of formula X are those wherein

-   R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl,    phenyl(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkyl, phenyl(C₂-C₆ alkynyl),    C₂-C₆ alkynyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, or    phenyl(C₁-C₆)alkanoyl,    -   wherein the phenyl groups are unsubstituted or substituted with        1, 2, 3, 4, or 5 groups that are independently halogen, C₁-C₄        alkyl, C₁-C₄ alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂H;        -   wherein the alkyl groups are unsubstituted or substituted            with 1, 2, or 3 groups that are independently halogen,            methoxy, ethoxy or spirocyclopropyl.

Other more preferred compounds of formula X are those wherein

-   R₂ is phenyl(C₁-C₆)alkoxy, phenyloxy, phenylthioalkoxy, C₁-C₈    alkoxy, alkyl, alkoxyalkoxy, —OC (O)NH(CH₂)_(n)pheny1,    —OC(O)N(alkyl) (CH₂)_(n)phenyl, dialkylamino, pyridyl, pyrimidyl,    pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl,    tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl,    triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl,    thiazolyl, thiophenyl, or CO₂H, wherein    -   n is 0, 1, 2, 3, 4, 5 or 6;    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen, NR₆R₇, haloalkyl,        haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, NR,R₇alkyl,        —OC(O)NR₆R₇, wherein        -   R₆ and R₇ are independently at each occurrence H, alkyl,            alkoxy, alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl,            wherein the aryl portion of arylalkyl, arylalkoxy, or            arylalkanoyl is unsubstituted or substituted with 1, 2, or 3            groups that are independently, halogen, alkoxy, alkyl,            haloalkyl, or haloalkoxy.

Still other more preferred compounds of formula X are those wherein

-   R₄ is H, (C₁-C₆)alkyl, phenyl(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkyl,    hydroxyalkyl, haloalkyl, NR₆R₇alkyl, alkoxy, alkoxyalkyl, or    alkoxyalkoxy, wherein    -   the phenyl groups are unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen, hydroxy, alkoxy,        alkyl, nitro, haloalkyl, or haloalkoxy.

Still other more preferred compounds of formula X are those wherein

-   R₅ is phenyl(C₁-C₆)alkyl, (C₁-C₆)alkyl, phenyl, alkoxy,    heterocycloalkylalkyl, naphthyl(C₁-C₆)alkyl, heteroarylalkyl,    heterocycloalkyl, or heteroaryl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        phenylalkoxy, thioalkoxy, alkoxycarbonyl, CO₂H, CN,        amidinooxime, NR₈R₉, NR₆R₇alkyl, —C(O)NR₆R₇, amidino, haloalkyl,        or haloalkoxy;        -   wherein R₈ is hydrogen, alkyl, alkanoyl, arylalkyl and            arylalkanoyl;        -   wherein R₉ is alkyl, alkanoyl, arylalkyl and arylalkanoyl;            provided that when R₂ is benzyloxy, and R₅ is benzyl or            methyl, R₁ is not hydrogen;

Still other more preferred compounds of formula X are those wherein

-   R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl,    phenyl(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkyl, CN, alkanoyl, ethynyl,    alkoxy, alkoxyalkyl, haloalkyl, or phenyl(C₁-C₆)alkanoyl,    -   -   wherein the phenyl groups are unsubstituted or substituted            with 1, 2, 3, 4, or 5 groups that are independently halogen,            C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H;        -   wherein the alkyl groups are unsubstituted or substituted            with 1, 2, or 3 groups that are independently halogen,            methoxy, or ethoxy;-   R₂ is phenyl(C₁-C₆)alkoxy, phenyloxy, phenylthioalkoxy, C₁-C₈    alkoxy, alkyl, alkoxyalkoxy, —OC(O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl)    (CH₂)_(n)phenyl, dialkylamino, pyridyl, pyrimidyl, pyridazyl,    pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl,    tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl,    triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl,    thiazolyl, thiophenyl, or CO₂H, wherein    -   n is 0, 1, 2, 3, 4, 5 or 6;    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen, NR₆R₇, haloalkyl,        haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, NR₆R₇alkyl,        —OC(O)NR₆R₇, wherein        -   R₆ and R₇ are independently at each occurrence H, alkyl,            alkoxy, alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl,            wherein the aryl portion of arylalkyl, arylalkoxy, or            arylalkanoyl is unsubstituted or substituted with 1, 2, or 3            groups that are independently, halogen, alkoxy, alkyl, CF₃,            OCF₃;-   R₄ is H, (C₁-C₆)alkyl, phenyl(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkyl,    hydroxyalkyl, haloalkyl, NR₆R₇alkyl, alkoxy, alkoxyalkyl, or    alkoxyalkoxy, wherein    -   the phenyl groups are unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen, hydroxy, alkoxy,        alkyl, nitro, CF₃, OCF₃; and-   R₅ is phenyl(C₁-C₆)alkyl, (C₁-C₆)alkyl, phenyl, alkoxy,    piperidinylalkyl, thienylalkyl, naphthyl(C₁-C₆)alkyl,    heteroarylalkyl, heterocycloalkyl, or heteroaryl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        phenylalkoxy, thioalkoxy, alkoxycarbonyl, CO₂H, CN,        amidinooxime, NR₈R₉, NR₆R₇alkyl, —C(O)NR₆R₇, amidino, CF₃, or        OCF₃;        -   wherein R₈ is hydrogen, alkyl, alkanoyl, arylalkyl and            arylalkanoyl;        -   wherein R₉ is alkyl, alkanoyl, arylalkyl and arylalkanoyl;            provided that when R₂ is benzyloxy, and R₅ is benzyl or            methyl, R₁ is not hydrogen.

Yet even more preferred compounds or salts of formula X are thosewherein

-   R₁ is H, halogen, alkyl, haloalkyl, carboxaldehyde, hydroxyalkyl,    phenyl(C₁-C₆)alkoxy, benzyl, phenethyl, phenpropyl, CN, or    phenyl(C₁-C₆)alkanoyl,    -   wherein the phenyl groups are unsubstituted or substituted with        1, 2, or 3 groups that are independently halogen, C₁-C₄ alkyl,        C₁-C₄ alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H;-   R₂ is benzyloxy, phenyloxy, phenylthioalkoxy, C₁-C₈,    —OC(O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl) (CH₂)_(n)phenyl,    dialkylamino, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl,    pyrrolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrazolyl,    pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl,    hexahydropyrimidinyl, thiazolyl, thiophenyl, or CO₂H, wherein    -   n is 0, 1, 2, 3, 4, 5 or 6;    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen, NR₆R₇, haloalkyl,        haloalkoxy, alkyl, heteroaryl, or NR₆R₇alkyl, wherein        -   R₆ and R₇ are independently at each occurrence H, alkyl,            alkoxy, alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl,            wherein the aryl portion of arylalkyl, arylalkoxy, or            arylalkanoyl is unsubstituted or substituted with 1, 2, or 3            groups that are independently, halogen, alkoxy, alkyl, CF₃,            OCF₃;-   R₄ is H, (C₁-C₆)alkyl, phenyl(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkyl,    hydroxyalkyl, wherein    -   the phenyl groups are unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen, hydroxy, alkoxy,        alkyl, nitro, CF₃, OCF₃; and-   R₅ is phenyl(C₁-C₆)alkyl₁ (C₁-C₆)alkyl, phenyl, piperidinylalkyl,    thienylalkyl, heteroaryl, naphthyl(C₁-C₆)alkyl, heteroarylalkyl, or    wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        benzyloxy, thioalkoxy, alkoxycarbonyl, CO₂H, CN, amidinooxime,        NR₈R₉, NR₆R₇alkyl, —C(O)NR₆R₇, amidino, CF₃, or OCF₃;        -   wherein R₈ is hydrogen, alkyl, alkanoyl, arylalkyl and            arylalkanoyl;        -   wherein R₉ is alkyl, alkanoyl, arylalkyl and arylalkanoyl;            provided that when R₂ is benzyloxy, and R₅ is benzyl or            methyl, R₁ is not hydrogen.

Still yet even more preferred compounds or salts of formula X are thosewherein

-   R₁ is H, halogen, alkyl or carboxaldehyde;-   R₂ is benzyloxy, phenyloxy, phenylthioalkoxy, or pyridyl; wherein    -   each of the above is unsubstituted or substituted with 1, 2, or        3, groups that are independently halogen, haloalkyl, or alkyl.

Other still yet even more preferred compounds of formula X are thosewherein

-   R₄ is H, (C₁-C₄)alkyl, phenyl(C₁-C₆)alkoxy, benzyl, phenyethyl,    phenpropyl, phenbutyl, hydroxy(C₁-C₆)alkyl, wherein the phenyl    groups are unsubstituted or substituted with 1, 2, or 3 groups that    are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF₃, OCF₃;    and-   R₅ is benzyl, phenethyl, phenpropyl, phenbutyl, (C₁-C₆)alkyl,    phenyl, pyridyl, pyrimidyl, naphthyl(C₁-C₆)alkyl,    thiophenyl(C₁-C₆)alkyl, or pyridyl(C₁-C₆)alkyl wherein    -   each of the above is unsubstituted or substituted with 1, 2, or        3 groups that are independently alkyl, halogen, alkoxy,        benzyloxy, thioalkoxy, alkoxycarbonyl, CO₂H, CN, amidinooxime,        CF₃ or OCF₃;        provided that when R₂ is benzyloxy, and R₅ is benzyl or methyl,        R₁ is not hydrogen.

Other still yet even more preferred compounds of formula X are thosewherein

-   R₁ is bromo, iodo, or H; and-   R₅ is benzyl, phenethyl, phenpropyl, phenyl, piperidinylalkyl,    thienylalkyl, —CH₂-pyridyl, or pyridyl, each of which is    unsubstituted or substituted with 1, 2, or 3 groups that are    independently C₁-C₄ alkyl, halogen, CF₃, OCF₃, —CO₂CH₃, C₁-C₄    alkoxy, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂(C₃-C₅ alkyl), benzyloxy, and    amidinooxime.

Even more preferred compounds of formula X are those wherein

-   R₂ is benzyloxy, or phenethyloxy,    -   each of the above is unsubstituted or substituted with 1, 2, or        3, groups that are independently fluoro, chloro, bromo, CF₃, or        (C₁-C₄)alkyl.

Other preferred compounds of formula X are those wherein

-   R₁ is halogen, alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy,    arylalkyl, CN, aryl, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, or    arylalkanoyl,    -   wherein the aryl portion of arylalkoxy, arylalkyl, and        arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or        5 groups that are independently halogen, (C₁-C₄)alkyl,        (C₁-C₄)alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂H;    -   wherein the alkyl portion of the alkyl, hydroxyalkyl,        arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and        arylalkanoyl groups is unsubstituted or substituted with 1, 2,        or 3 groups that are independently halogen, methoxy, ethoxy or        spirocyclopropyl;-   R₂ is arylalkoxy, OH, aryloxy, arylthioalkoxy, alkoxy,    —OC(O)NH(CH₂)_(n)aryl, —OC(O)N(alkyl) (CH2)aryl, alkyl,    alkoxyalkoxy, NR₆R₇, pyridyl, pyrimidyl, pyridazyl, pyrazolyl,    imidazolyl, pyrrolyl, tetrahydroquinolinyl, amino,    tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl,    arylalkyl, triazinyl, tetrahydrofuryl, piperidinyl,    hexahydropyrimidinyl, thiazolyl, thiophenyl, or CO₂H, wherein    -   n is 0, 1, 2, 3., 4, 5 or 6;    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen, NR₆R₇, haloalkyl,        haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, -so₂phenyl        wherein the phenyl is optionally substituted with 1 or 2 groups        that are independently halogen or NO2; NR₆R₇alkyl, —OC(O)NR₆R₇,        wherein        -   R₆ and R₇ are. independently at each occurrence H, alkyl,            alkoxy, alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl,            wherein the aryl portion of each of the above is            unsubstituted or substituted with 1, 2, or 3 groups that are            independently, halogen, alkoxy, alkyl, haloalkyl, or            haloalkoxy;-   R₄ is H, alkyl, arylalkoxy, arylalkyl, hydroxyalkyl, haloalkyl,    NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the aryl    portion of arylalkoxy, arylalkyl is unsubstituted    or substituted with 1, 2, 3, 4, or 5 groups that are independently    halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy;    and-   R₅ is arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl,    heteroarylalkyl, heterocycloalkyl, or heteroaryl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl,        CO₂H, CN, amidinooxime, NR₈R₉, NR₆R₇alkyl, —C(O)NR₆R₇, amidino,        haloalkyl, or haloalkoxy;        -   wherein R₈ is hydrogen, alkyl, alkanoyl, arylalkyl and            arylalkanoyl; and        -   wherein R₉ is alkyl, alkanoyl, arylalkyl and arylalkanoyl;            provided that when R₂ is OH, R₄ is methyl and R₅ is phenyl,            R₁ is not acetyl.

More preferred compounds of formula X are those wherein

-   R₁ is halogen, alkyl, carboxaldehyde, hydroxyalkyl, phenylalkoxy,    phenylalkyl, CN, alkanoyl, phenyl, alkoxy, alkoxyalkyl, haloalkyl,    or phenylalkanoyl,    -   wherein the above phenyl groups are unsubstituted or substituted        with 1, 2, 3, 4, or 5 groups that are independently halogen,        (C₁-C₄)alkyl, (C₁-C₄) alkoxy, nitro, CN, haloalkyl, haloalkoxy        or CO₂H;        -   wherein the above alkyl groups are unsubstituted or            substituted with 1, 2, or 3 groups that are independently            halogen, methoxy, or ethoxy.

Other more preferred compounds of formula X are those wherein

-   R₂ is phenylalkoxy, OH, phenyloxy, phenylthioalkoxy, alkoxy,    —OC(O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl) (CH₂)_(n)phenyl, NR₆R₇,    alkyl, dialkylamino, pyridyl, pyrimidyl, pyridazyl, pyrazolyl,    imidazolyl, pyrrolyl, tetrahydroquinolinyl, amino,    tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl,    phenyl(C₁-C₆ alkyl), triazinyl, tetrahydrofuryl, piperidinyl,    hexahydropyrimidinyl, thiazolyl, thiophenyl, or CO₂H, wherein    -   n is 0, 1, 2, 3, 4, 5 or 6;    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen, NR₆R₇ haloalkyl,        haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, or NR₆R₇alkyl1        wherein        -   R₆ and R₇ at each occurrence are independently H, alkyl,            alkoxy, alkanoyl, phenylalkyl, phenylalkoxy, or            phenylalkanoyl, wherein the above phenyl groups are            unsubstituted or substituted with 1, 2, or 3 groups that are            independently, halogen, alkoxy, alkyl, haloalkyl, or            haloalkoxy.

Still other more preferred compounds of formula X are those wherein

-   R₄ is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl,    NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein    -   the above phenyl groups are unsubstituted or substituted with 1,        2, 3, 4, or 5 groups that are independently halogen, hydroxy,        alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy.

Still other more preferred compounds of formula-X are those wherein

-   R₅ is phenylalkyl, (C₁-C₆)alkyl, phenyl, naphthyl, alkoxy,    piperidinyl, pyrolidinyl, imidazolidinyl, piperazinyl,    tetrahydropyranyl, piperidinyl(C₁-C₆)alkyl, pyrolidinyl(C₁-C₆)alkyl,    imidazolidinyl(C₁-C₆)alkyl, piperazinyl(C₁-C₆)alkyl,    tetrahydropyranyl(C₁-C₆)alkyl, pyridyl, pyrimidyl, pyridazyl,    pyrazinyl, pyridyl(C₁-C₆)alkyl, pyrimidyl(C₁-C₆)alkyl,    pyridazyl(C₁-C₆)alkyl, or pyrazinyl(C₁-C₆)alkyl wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        phenylalkoxy, thioalkoxy, alkoxycarbonyl, phenylalkoxycarbonyl,        CO₂H, CN, amidinooxime, NR₈R₉, NR₆R₇alkyl, —C(O)NR₆R₇, amidino,        haloalkyl, or haloalkoxy;        -   wherein RB and R₉ are independently hydrogen, alkyl,            alkanoyl, phenylalkyl and phenylalkanoyl;            provided that when R₂ is OH, R₄ is methyl and R₅ is phenyl,            R₁ is not acetyl.

Still other more preferred compounds of formula X are those wherein

-   R₁ is halogen, alkyl, carboxaldehyde, hydroxyalkyl, phenyl,    phenylalkoxy, phenylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl,    haloalkyl, or phenylalkanoyl,    -   wherein the above phenyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen,        (C₁-C₄)alkyl, (C₁-C₄)alkoxy, nitro, CN, haloalkyl, haloalkoxy or        CO₂H;    -   wherein the above alkyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen, methoxy,        or ethoxy,-   R₂ is phenylalkoxy, OH, phenyloxy, phenylthio(C₁-C₄ alkoxy), alkoxy,    —OC(O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl) (CH₂)_(n)phenyl, alkyl,    alkoxyalkoxy, NR₆R₇, pyridyl, pyrimidyl, pyridazyl, pyrazolyl,    imidazolyl, pyrrolyl, phenethyl, tetrahydroquinolinyl, amino,    tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl,    triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl,    thiazolyl, thiophenyl, or CO₂H, wherein    -   n is 0, 1, 2, or 3;    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen, haloalkyl,        haloalkoxy, alkyl, thiophenyl, or pyridyl;-   R₆ and R₇ are independently at each occurrence H, alkyl, alkoxy,    alkanoyl, benzyl, arylalkoxy, or arylalkanoyl, wherein the aryl    portion of each of the above is unsubstituted or substituted with 1,    2, or 3 groups that are independently, halogen, alkoxy, alkyl, CF₃,    or OCF₃;-   R₄ is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl,    NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein    -   the above phenyl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently halogen, hydroxy, alkoxy,        alkyl, nitro, haloalkyl, or haloalkoxy; and-   R₅ is benzyl, phenethyl, (C₁-C₆)alkyl, phenyl, naphthyl, alkoxy,    piperidinyl, pyrolidinyl, imidazolidinyl, piperazinyl,    piperidinyl(C₁-C₆)alkyl, pyrolidinyl(C₁-C₆)alkyl,    imidazolidinyl(C₁-C₆)alkyl, pyridyl, pyrimidyl, pyridazyl,    pyrazinyl, pyridyl(C₁-C₆)alkyl, pyrimidyl(C₁-C₆)alkyl,    pyridazyl(C₁-C₆)alkyl, or pyrazinyl(C₁-C₆)alkyl wherein    -   each of the above is unsubstituted or substituted with 1, 2, or        3 groups that are independently alkyl, halogen, alkoxy,        phenylalkoxy, thioalkoxy, alkoxycarbonyl, phenylalkoxycarbonyl,        CO₂H, CN, amidinooxime, NR₈R₉, NR₆R₇alkyl, —C(O)NR₆R₇, amidino,        haloalkyl, or haloalkoxy;        -   wherein R₈ and R₉ are independently hydrogen, alkyl,            alkanoyl, phenylalkyl and phenylalkanoyl;            provided that when R₂ is OH, R₄ is methyl and R₅ is phenyl,            R₁ is not acetyl.

Still yet more preferred compounds of formula X are those wherein

-   R₁ is halogen, alkyl, carboxaldehyde, hydroxyalkyl, phenylalkoxy,    phenyl, benzyl, phenethyl, phenpropyl, phenbutyl, CN,    (C₂-C₆)alkanoyl, haloalkyl, or phenylCO—, phenylCH₂CO—,    phenylCH₂CH₂CO—,    -   wherein the above phenyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen,        (C₁-C₄)alkyl, (C₁-C₄) alkoxy, nitro, CN, haloalkyl, haloalkoxy        or CO₂H;    -   wherein the above alkyl groups are unsubstituted or substituted        with 1, 2, or 3 groups, that are independently halogen, methoxy,        or ethoxy,-   R₂ is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy,    phenylthio(C₁-C₄)alkoxy, phenethyl, NR₆R₇, (C₁-C₆)alkyl,    alkoxyalkoxy, piperidinyl, —OC(O)N(CH₃)CH₂phenyl, pyridyl,    pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl,    hexahydropyrimidinyl, benzimidazolyl, or thiophenyl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, or        3 groups that are independently halogen, CF₃, OCF₃,        (C₁-C₄)alkyl, thiophenyl, or pyridyl;    -   R₆ and R₇ are independently at each occurrence H, alkyl, alkoxy,        alkanoyl, phenylalkyl, phenylalkoxy, or phenylalkanoyl, wherein        the phenyl portion of each of the above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, alkoxy, alkyl, CF₃, or OCF₃;-   R₄ is H, alkyl, benzyloxy, phenethyloxy, phenpropyloxy, benzyl,    phenethyl, phenpropyl, hydroxyalkyl, halo(C₁-C₄)alkyl, NR₆R₇alkyl,    alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the above phenyl    groups are unsubstituted or substituted with 1, 2, or 3 groups that    are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF₃ or    OCF₃; and-   R₅ is benzyl, phenethyl, phenpropyl, phenbutyl, (C₁-C₆)alkyl,    phenyl, piperidinyl, pyrolidinyl, imidazolidinyl, piperazinyl,    piperidinyl(C₁-C₆)alkyl, pyrolidinyl(C₁-C₆)alkyl,    imidazolidinyl(C₁-C₆)alkyl, pyridyl, pyrimidyl, pyridazyl,    pyrazinyl, pyridyl(C₁-C₆)alkyl, pyrimidyl(C₁-C₆)alkyl,    pyridazyl(C₁-C₆)alkyl, or pyrazinyl(C₁-C₆)alkyl wherein    -   each of the above is unsubstituted or substituted with 1, 2, or        3 groups that are independently alkyl, halogen, alkoxy,        phenylalkoxy, thioalkoxy, alkoxycarbonyl, phenylalkoxycarbonyl,        CO₂H, CN, amidinooxime, amidino, CF₃, CF₂CF₃, ClCH₂, or OCF₃;        provided that when R₂ is OH, R₄ is methyl and R₅ is phenyl, R₁        is not acetyl.

Still yet more preferred compounds of formula X are those wherein

-   R₁ is halogen, alkyl, carboxaldehyde, hydroxy(C₁-C₄)alkyl,    phenylalkoxy, benzyl, phenethyl, —C(O)CH₃, phenylCO—, or    phenylCH₂CO—,    -   wherein the above phenyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen,        (C₁-C₄)alkyl, (C₁-C₄) alkoxy, nitro, CN, CF₃, or OCF₃;    -   wherein the above alkyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen, methoxy,        or ethoxy;-   R₂ is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy, NR₆R₇,    —S-benzyl, or (C₁-C₆)alkyl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, or        3 groups that are independently halogen, CF₃, OCF₃, alkyl,        thiophenyl, or pyridyl;    -   R₆ and R₇ are independently at each occurrence H, alkyl,        alkanoyl, benzyl, benzyloxy, or phenylalkanoyl, wherein the        phenyl portion of each of the above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, alkoxy, alkyl, CF₃, or OCF₃;-   R₄ is H, alkyl, benzyloxy, phenethyloxy, phenpropyloxy, benzyl, or    hydroxyalkyl, wherein    -   the above phenyl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently halogen, hydroxy, alkoxy,        alkyl, nitro, CF₃ or OCF₃; and-   R₅ is benzyl, phenethyl, phenpropyl, phenbutyl, (C₁-C₆)alkyl,    phenyl, pyridyl, or pyridyl, (C₁-C₄)alkyl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, or        3 groups that are independently alkyl, halogen, (C₁-C₄)alkoxy,        phenyl(C₁-C₄)alkoxy, thio (C₁-C₄)alkoxy, alkoxycarbonyl, OH,        CO₂H, CN, amidinooxime, amidino, CF₃, or OCF₃.

Still yet more preferred compounds of formula X are those wherein

-   R₁ is halogen, alkyl, carboxaldehyde, or hydroxyalkyl;-   R₂ is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy,    phenylthioalkoxy, or (C₁-C₆)alkyl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, or        3 groups that are independently halogen, CF₃, OCF₃, alkyl,        thiophenyl, or pyridyl;-   R₄ is H, (C₁-C₄)alkyl, benzyloxy, phenethyloxy, wherein    -   the above phenyl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently halogen, hydroxy,        (C₁-C₄)alkoxy, (C₁-C₄)alkyl, nitro, CF₃ or OCF₃; and-   R₅ is benzyl, phenethyl, (C₁-C₆)alkyl, phenyl, or pyridyl, wherein    each of the above is unsubstituted or substituted with 1, 2, or 3    groups that are independently (C₁-C₄)alkyl, halogen, OH, CO₂H, CN,    (C₁-C₄)alkoxy, benzyloxy, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂(C₃-C₅ alkyl),    amidino, thio(C₁-C₆)alkoxy, amidinooxime, CF₃, or OCF₃.

Still yet more preferred compounds of formula X are those wherein

-   R₁ is bromo; and-   R₅is benzyl, phenethyl, phenpropyl, phenyl, or pyridyl, each of    which is unsubstituted or substituted with 1, 2, or 3 groups that    are independently alkyl, halogen, alkoxy, and amidinooxime.

Still yet even more preferred compounds of formula X are those wherein

-   R₂ is benzyloxy, or phenethyloxy, each of which is unsubstituted or    substituted with 1, 2, or 3 groups that are independently halogen,    CF₃, OCF₃, or (C₁-C₄)alkyl.

A pharmaceutical composition comprising at least one pharmaceuticallyacceptable carrier, solvent, adjuvant or excipient and a compoundaccording to formula X.

The present invention comprises a pharmaceutical composition for thetreatment of a TNF mediated disorder, a p38 kinase mediated disorder,inflammation, and/or arthritis, comprising a therapeutically-effectiveamount of a compound of Formula I, or a therapeutically-acceptable saltor tautomer thereof, in association with at least onepharmaceutically-acceptable carrier, adjuvant, solvent, excipient, ordiluent.

The present invention also comprises a therapeutic method of treating aTNF mediated disorder, a p38 kinase mediated disorder, inflammationand/or arthritis in a subject, the method comprising treating a subjecthaving or susceptible to such disorder or condition with atherapeutically-effective amount of a compound of Formula I and/orFormula X.

Specific diseases or conditions that may be treated using compounds ofFormula I, Formula III, Formula IV, and/or Formula X include:

inflammation;

arthritis, including but not limited to, rheumatoid arthritis,spondylarthropathies, gouty arthritis, gouty arthritis, osteoarthritis,systemic lupus erthematosus and juvenile arthritis, osteoarthritis,gouty arthritis and other arthritic conditions;

neuroinflammation;

pain (i.e., use as an analgesic) including but not limited toneuropathic pain;

fever (i.e., use as an antipyretic);

pulmonary disorders or lung inflammation, including adult respiratorydistress syndrome, pulmonary sarcoisosis, asthma, silicosis, and chronicpulmonary inflammatory disease;

cardiovascular diseases including arteriosclerosis, myocardialinfarction, thrombosis, congestive heart failure, and cardiacreperfusion injury;

cardiomyopathy;

reperfusion injury;

renal reperfusion injury;

ischemia including stroke and brain ischemia;

brain trauma;

brain edema;

liver disease and nephritis;

gastrointestinal conditions such as inflammatory bowel disease, Crohn'sdisease, gastritis, irritable bowel syndrome and ulcerative colitis;

ulceratiuve diseases such as gastric ulcer;

ulcerative diseases such as gastric ulcer;

ophthalmic diseases such as retinitis, retinopathies, uveitis, ocularphotophobia, and of acute injury to the eye tissue;

ophthalmological conditions such as corneal graft rejection, ocularneovascularization, retinal neovascularization includingneovascularization following injury or infection, diabetic retinopathy,retrolental fibroplasias and neovascular glaucoma;

diabetes;

diabetic nephropathy;

skin-related conditions such as psoriasis, eczema, burns, dermatitis,keloid formation, scar tissue formation, and angiogenic disorders;

viral and bacterial infections, including sepsis, septic shock, gramnegative sepsis, malaria, meningitis, opportunistic infections, cachexiasecondary to infection or malignancy, cachexia secondary to acquiredimmune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex),pneumonia, and herpes virus;

myalgias due to infection;

influenza;

endotoxic shock;

toxic shock syndrome;

autoimmune disease including graft vs. host reaction and allograftrejections;

treatment of bone resorption diseases, such as osteoporosis;

multiple sclerosis;

disorders of the female reproductive system such as endometriosis;

pathological, but non-malignant, conditions such as hemaginomas,including infantile hemagionmas, angiofibroma of the nasopharynz andavascular necrosis of bone;

benign and malignant tumors/neoplasia including cancer, such ascolorectal cancer, brain cancer, bone cancer, epithelial call-derivedneoplasia (epithelial carcinoma) such as basal cell carcinoma,adenocarcinoma, gastrointestinal cancer such as lip cancer, mouthcancer, esophageal cancer, small bowel cancer and stomach cancer, coloncancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer,cervical cancer, lung cancer, breast cancer and skin cancer, such assquamus cell and basal cell cancers, prostate cancer, renal cellcarcimoma, and other known cancers that affect epithelial cellsthroughout the body;

leukemia;

lymphoma;

systemic lupus erthrematosis (SLE);

angiogenesis including neoplasia;

metastasis; and

central nervous system disorders (including, but not limited to, centralnervous system disorders having an inflammatory or apoptotic component),such as Alzheimer's disease, Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis, spinal cord injury, and peripheralneuropathy.

The invention also covers a method of treating a p38 kinase or TNF-alphamediated disorder comprising administering to a patient in need thereofa therapeutically effective amount of any of the preceding compounds andat least one pharmaceutically acceptable carrier, adjuvant, solvent orexcipient.

The following compounds of the invention are meant to give the reader anunderstanding of the compounds falling within the invention;

1-benzyl-4-(benzyloxy)-3-bromopyridin-2(1H) -one;

3-bromo-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-dimethylphenyl)-6-methylpyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-(4-fluorobenzyl)pyridin-2(1H)-one;

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H)-one;

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;

4-bromo-2-(2,6-dichlorophenyl)-5-[(2,4-difluorobenzyl)oxy]pyridazin-3(2H)-one;

3-bromo-1-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;

3-bromo-1-(3-fluorobenzyl)-4-[(3-methylbenzyl)oxy]pyridin-2(1H)-one;

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one;

1-benzyl-4-(benzyloxy)-3-bromo-6-methylpyridin-2(f1H)-one;

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-methoxy-6-methylphenyl)-6-methylpyridin-2(1H)-one;

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-fluorobenzyl)pyridin-2(1H)-one;

3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;

3-bromo-1-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-(4-methylbenzyl)pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-(4-chlorobenzyl)pyridin-2(1H)-one;

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-methoxybenzyl)pyridin-2(1H)-one;

4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoic acid;

4-(benzyloxy)-3-bromo-1-(2-fluorobenzyl)pyridin-2(1H)-one;

3-bromo-1-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H) -one;

4-(benzyloxy)-3-bromo-1-[4-(methylthio)benzyl]pyridin-2(1H)-one;

1-benzyl-4-(benzyloxy)-3-chloropyridin-2(1H)-one;

4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}-N′-hydroxybenzenecarboximidamide;

methyl 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoate;

3-bromo-4-[(3-chlorobenzyl)oxy]-1-1-(3-fluorobenzyl)pyridin-2(1H)-one;

3-bromo-1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;

4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;

4-(benzyloxy)-3-bromo-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one;

3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-(4-bromobenzyl)pyridin-2(1H)-one;

4-{[3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;

1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-2(1H)-one;

4-bromo-2-(2,6-dichlorophenyl)-5-{[2-(hydroxymethyl)benzyl]oxy}pyridazin-3(2H)-one;

3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;

3-bromo-1-(2,4-difluorobenzyl)-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;

3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-2-ylmethyl)pyridin-2(1H)-one;

2-benzyl-5-(2,6-dichlorophenyl)-3,4-dimethyl-1,5-dihydro-6H-pyrrolo[3,2-c]pyridin-6-one;

3-bromo-4-[(4-chlorobenzyl)oxy]-1-(4-fluorobenzyl)pyridin-2(1H)-one;

1-benzyl-3-bromo-4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one;

3-bromo-1-(4-chlorobenzyl)-4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one;

3-bromo-4-[(4-chlorobenzyl)oxy]-1-[2-(phenylthio)ethyl]pyridin-2(1H)-one;

3-bromo-4-[(4-chlorobenzyl)oxy]-1-(2-phenylethyl)pyridin-2(1H)-one;

3-bromo-4-hydroxy-1-(4-hydroxybenzyl)pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-(piperidin-3-ylmethyl)pyridin-2(1H)-onehydrochloride;

3-bromo-1-(4-methoxybenzyl)-4-phenoxypyridin-2(1H)-one;

1-benzyl-2-oxo-4-phenoxy-1,2-dihydropyridine-3-carbaldehyde;

3-bromo-4-[(4-chlorobenzyl)oxy]-1-(4-methoxybenzyl)pyridin-2(1H)-one;

3-bromo-4-[(4-fluorobenzyl)oxy]-1-(3-phenylpropyl)pyridin-2(1H)-one;

4-(benzyloxy)-1-[4-(benzyloxy)benzyl]-3-bromopyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-[2-(trifluoromethyl)benzyl]pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-[3-(trifluoromethyl)benzyl]pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-(piperidin-4-ylmethyl)pyridin-2(1H)-onehydrochloride;

1-benzyl-4-(benzylthio)-3-bromopyridin-2(1H)-one;

1-benzyl-3-bromo-4-{[2-(trifluoromethyl)benzyl]oxy}pyridin-2(1H)-one;

1-benzyl-4-[(2,6-dichlorobenzyl)oxy]pyridin-2(1H)-one;

1-benzyl-4-(benzyloxy)-3-(hydroxymethyl)pyridin-2(1H)-one;

1-benzyl-3-bromo-4-[(2,6-dichlorobenzyl)oxy]pyridin-2(1H)-one;

1-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;

1-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;

1-benzyl-3-bromo-4-[(2-chlorobenzyl)oxy]pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-ethylpyridin-2(1H)-one;

4-(benzyloxy)-1-(4-bromobenzyl)pyridin-2(1H)-one;

3-bromo-1-(4-methylbenzyl)-4-[(4-methylbenzyl)oxy]pyridin-2 (1H) -one;

methyl 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoate;

4-(benzyloxy)-3-bromo-1-(2-thien-3-ylethyl)pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-(2-thien-2-ylethyl)pyridin-2(1H)-one;

1-benzyl-4-[(3-chlorobenzyl)oxy]pyridin-2(1H)-one;

3-bromo-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;

4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one;

4-(benzyloxy)-1-(2-fluorobenzyl)pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-methylpyridin-2(1H)-one hydrobromide;

4-(benzyloxy)-3-bromo-1-methylpyridin-2(1H)-one;

3-bromo-1-(3-chlorobenzyl)-4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one;

3-bromo-1-(3-chlorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;

4-(benzyloxy)-1-(4-chlorobenzyl)pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-[4-(trifluoromethoxy)benzyl]pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-(4-tert-butylbenzyl)pyridin-2(1H)-one;

1-benzyl-4-(benzyloxy)-6-methylpyridin-2(1H)-one

1-benzyl-4-(benzyloxy)-3,5-dibromo-6-methylpyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-[4-(trifluoromethyl)benzyl]pyridin-2(1H)-one;

1-benzyl-4-[(2-chlorobenzyl)oxy]pyridin-2(1H)-one;

1-(2-bromobenzyl)-3-[(2-bromobenzyl)oxy]pyridin-2(1H)-one;

methyl5-chloro-1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridine-3-carboxylate;

3-benzyl-4-hydroxy-1-(2-phenylethyl)pyridin-2(1H)-one;

5-bromo-1-(2-chloro-6-fluorobenzyl)-3-methylpyridin-2(1H)-one;

1-(2-bromobenzyl)-3-[(2-bromobenzyl)oxy]pyridin-2(1H)-one;

1-benzyl-4-(benzyloxy)pyridin-2(1H)-one;

1-benzyl-4-(benzyloxy)-3-bromopyridin-2(1H)-one;

1-benzyl-4-(benzyloxy)-2-oxo-1,2-dihydropyridine-3-carbaldehyde;

1-benzyl-4-chloro-2-oxo-1,2-dihydropyridine-3-carbaldehyde;

1-benzyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carbaldehyde;

1-benzyl-4-(benzyloxy)-3-methylpyridin-2(1H)-one;

4-(benzyloxy)-1-(4-fluorobenzyl)pyridin-2(1H)-one;

1-benzyl-4-(benzyloxy)-3,5-dibromopyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-[4-(methylthio)benzyl]pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-(4-fluorobenzyl)pyridin-2(1H)-one;

1-benzyl-4-(benzyloxy)-3-chloropyridin-2(1H)-one;

3-bromo-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;

5-benzyl-1,2,7-trimethyl-3-(phenylthio)-1,5-dihydro-6H-pyrrolo[3,2-c]pyridin-6-one;

1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl methyl(phenyl)carbamate;

1-benzyl-3-bromo-4-(2-phenylethyl)pyridin-2(1H)-one;

1-benzyl-3-bromo-4-(3-phenylpropyl)pyridin-2(1H)-one;

1-benzyl-3-methyl-4-(2-phenylethyl)pyridin-2(1H)-one;

1-benzyl-3-methyl-4-(3-phenylpropyl)pyridin-2(1H)-one;

1-benzyl-4-(benzylthio)-3-methylpyridin-2(1H)-one;

1-benzyl-4-(benzylthio)-3-bromopyridin-2(1H)-one;

(product) 1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methanesulfonate;

3-acetyl-4-hydroxy-6-methyl-1-[choro]phenylpyridin-2(1H)-one;

6-(benzyloxy)-1-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile;

3-benzoyl-6-(benzyloxy)-1-methylpyridin-2(1H)-one;

3-benzyl-6-(benzyloxy)-1-methylpyridin-2(1H)-one;

1-benzyl-4-hydroxypyridin-2(1H)-one;

1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methanesulfonate;

1-benzyl-4-(benzylthio)pyridin-2(1H)-one1-benzyl-4-(benzylthio)-3-bromopyridin-2(1H)-one;

1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methanesulfonate;

4-amino-1-benzylpyridin-2(1H)-one;

1-benzyl-4-(benzyloxy)pyridin-2(1H)-one;

1-benzyl-4-hydroxypyridin-2(1H)-one;

1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methyl(phenyl)carbamate;

4-(benzyloxy)-1-(4-methylbenzyl)pyridin-2(1H)-one;

4-(benzyloxy)-3-bromopyridin-2(1H)-one;

methyl 4-{[4-(benzyloxy)-2-oxopyridin-1(21)-yl]methyl} benzoate;

methyl-4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl} benzoate;

4-{[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]methyl} benzonitrile;

4-(benzyloxy)-1-(4-tert-butylbenzyl)pyridin-2(1H)-one;

4-(benzyloxy)-1-[4-(trifluoromethyl)benzyl]pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-[4-(trifluoromethyl) benzyl]pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-[3-(trifluoromethyl) benzyl]pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-[2-(trifluoromethyl) benzyl]pyridin-2(1H)-one;

4-(benzyloxy)-1-[4-(trifluoromethoxy)benzyl]pyridin-2(1H)-one;

4-(benzyloxy)-3-bromo-1-[4-(trifluoromethoxy) benzyllpyridin-2(1H)-one;

1-benzyl-4-hydroxy-6-methylpyridin-2(1H)-one;

1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl 4-bromobenzenesulfonate;

1-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;

1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl 4-bromobenzenesulfonate;

1-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;

1-Benzyl-4-[2,6-(dichlorobenzyl)oxy]pyridin-2(1H)-one;

4-[(2,6-dichlororbenzyl)oxy]pyridine-1-oxide;

4-[(2,6-dichlorobenzyl)oxy]pyridine 1-oxide;

1-Benzyl-3-bromo-4-[2,6-(dichlorobenzyl)oxy]pyridin-2(1H)-one;

1-Benzyl-3-bromo-4-[(4-methylbenzyl)oxy]pyridin-2(1H)-one;

1-Benzyl-4-[benzylthio]-3-bromopyridin-2(1H)-one;

1-benzyl-4-(benzyloxy)-3-iodopyridin-2(1H)-one;

1-benzyl-4-(benzyloxy)-3-vinylpyridin-2(1H)-one;

1-benzyl-4-(benzyloxy)-3-ethylpyridin-2(1H)-one;

3-acetyl-4-(benzyloxy)-1-(2-chlorophenyl)-6-methylpyridin-2(1H)-one;

3-acetyl-1-(2-chlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one;

1-benzyl-3-bromo-4-hydroxypyridin-2(1H)-one;

1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate;

1-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(1H)-one;

3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(2-phenylethyl)pyridin-2(1H)-one;

1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one;

3-bromo-1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one;

3-bromo-1-(3-fluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate;

3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(phenylethynyl)pyridin-2(1H)-one;

3-acetyl-1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one;

1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one;

4-(benzyloxy)-1-(2,6-dichlorophenyl)-6-methylpyridin-2(l1)-one;

3-bromo-1-(3-fluorobenzyl)-4-(2-phenylethyl)pyridin-2(1H)-one;

3-bromo-1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one;

3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate;

3-bromo-1-(3-fluorobenzyl)-4-(phenylethynyl)pyridin-2(1H)-one;

4-(benzyloxy)-3-ethynyl-1-(3-fluorobenzyl)pyridin-2(1H)-one;

4-(benzyloxy)-1-(3-fluorobenzyl) -3-iodopyridin-2(1H) -one;

4-(benzyloxy)-1-(3-fluorobenzyl)-3-[(trimethylsilyl)ethynyl]pyridin-2(1H)-one;

4-(benzylamino)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one;

1-(3-fluorobenzyl) -4-hydroxypyridin-2 (1H)-one;

4-(benzylamino)-1-(3-fluorobenzyl)pyridin-2(1H)-one;

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-fluorobenzyl)pyridin-2(1H)-one;

3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H) -one;

3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;

3-bromo-1-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-methoxybenzyl)pyridin-2(1H)-one;

3-bromo-1-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;

3-bromo-4-[(3-chlorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(11)-one;

3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;

3-bromo-1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H) -one;

4-{[3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;

1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-2(1H) -one;

3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;

3-bromo-1-(2,4-difluorobenzyl)-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;

3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-2-ylmethyl)pyridin-2(11)-one;

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H)-one;

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;

3-bromo-1-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;

3-bromo-1-(3-fluorobenzyl)-4-[(3-methylbenzyl)oxy]piperidin-2-one;

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-methoxy-6-methylphenyl)-6-methylpyridin-2(1H)-one;or a pharmaceutically acceptable salt thereof.

Definitions

As used herein, the term “alkenyl”, refers to a straight or branchedhydrocarbon of a designed number of carbon atoms containing at least onecarbon-carbon double bond. Examples of “alkenyl”, include vinyl, allyl,and 2-methyl-3-heptene.

The term “alkoxy” represents an alkyl attached to the parent molecularmoiety through an oxygen bridge. Examples of alkoxy groups include, forexample, methoxy, ethoxy, propoxy and isopropoxy.

The term “thioalkoxy” represents an alkyl attached to the parentmolecular moiety through a sulfur atom. Examples of thioalkoxy groupsinclude, for example, thiomethoxy, thioethoxy, thiopropoxy andthioisopropoxy.

As used herein, the term “alkyl” includes those alkyl groups of adesigned number of carbon atoms. Alkyl groups may be straight orbranched. Examples of “alkyl” include methyl, ethyl, propyl, isopropyl,butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl,and the like. “Cx-Cy alkyl” represents an alkyl group of the specifiednumber of carbons. For example, C₁-C₄ alkyl includes all alkyl groupsthat include at least one and no more than four carbon atoms. It alsocontains subgroups, such as, for example, C₂-C₃ alkyl or C₁-C₃ alkyl.

The term “aryl” refers to an aromatic hydrocarbon ring system containingat least one aromatic ring. The aromatic ring may optionally be fused orotherwise attached to other aromatic hydrocarbon rings or non-aromatichydrocarbon rings. Examples of aryl groups include, for example, phenyl,naphthyl, 1,2,3,4-tetrahydronaphthalene, indanyl, and biphenyl.Preferred examples of aryl groups include phenyl and naphthyl. The mostpreferred aryl group is phenyl.

The term “alarylalkyl” refers to an aryl group, as defined above,attached to the parent molecular moiety through an alkyl group, asdefined above. Preferred arylalkyl groups include, benzyl, phenethyl,phenpropyl, and phenbutyl. More preferred arylalkyl groups includebenzyl and phenethyl. The most preferred arylalkyl group is benzyl.

The term “arylalkoxy” refers to an aryl group, as defined above,attached to the parent molecular moiety through an alkoxy group, asdefined above. Preferred arylaloxy groups include, benzyloxy,phenethyloxy, phenpropyloxy, and phenbutyloxy. The most preferredarylalkoxy group is benzyloxy.

The term “cycloalkyl” refers to a C₃-C₈ cyclic hydrocarbon. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. More preferred cycloalkyl groups includecyclopropyl.

The term “cycloalkylalkyl,” as used herein, refers to a C₃-C₈ cycloalkylgroup attached to the parent molecular moiety through an alkyl group, asdefined above. Examples of cycloalkylalkyl groups includecyclopropylmethyl and cyclopentylethyl.

The terms “halogen” or “halo,” indicate fluorine, chlorine, bromine, oriodine.

The term “heterocycloalkyl,” refers to a non-aromatic ring systemcontaining at least one heteroatom selected from nitrogen, oxygen, andsulfur, wherein the non-aromatic heterocycle is attached to the core.The heterocycloalkyl ring may be optionally fused to or otherwiseattached to other heterocycloalkyl rings, aromatic heterocycles,aromatic hydrocarbons and/or non-aromatic hydrocarbon rings. Preferredheterocycloalkyl groups have from 3 to 7 members. Examples ofheterocycloalkyl groups include, for example, piperazine,1,2,3,4-tetrahydroisoquinoline, morpholine, piperidine, tetrahydrofuran,pyrrolidine, and pyrazole. Preferred heterocycloalkyl groups includepiperidinyl, piperazinyl, morpholinyl, and pyrolidinyl.

The term “heteroaryl” refers to an aromatic ring system containing atleast one heteroatom selected from nitrogen, oxygen, and sulfur. Theheteroaryl ring may be fused or otherwise attached to one or moreheteroaryl rings, aromatic or non-aromatic hydrocarbon rings orheterocycloalkyl rings. Examples of heteroaryl groups include, forexample, pyridine, furan, thiophene, 5,6,7, 8-tetrahydroisoquinoline andpyrimidine. Preferred examples of heteroaryl groups include thienyl,benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl,benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl,isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl,tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl. Preferredheteroaryl groups include pyridyl.

As used herein, the term “p38 mediated disorder” refers to any and alldisorders and disease states in which p38 plays a role, either bycontrol of p38 itself, or by p38 causing another factor to be released,such as but not limited to IL-1, IL-6 or IL-8. A disease state in which,for instance, IL-1 is a major component, and whose production or action,is exacerbated or secreted in response to p38, would therefore beconsidered a disorder mediated by p38.

As TNF-beta has close structural homology with TNF-alpha (also known ascachectin), and since each induces similar biologic responses and bindsto the same cellular receptor, the synthesis of both TNF-alpha andTNF-beta are inhibited by the compounds of the present invention andthus are herein referred to collectively as “TNF” unless specificallydelineated otherwise.

Non-toxic pharmaceutically acceptable salts include, but are not limitedto salts of inorganic acids such as hydrochloric, sulfuric, phosphoric,diphosphoric, hydrobromic, and nitric or salts of organic acids such asformic, citric, malic, maleic, fumaric, tartaric, succinic, acetic,lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic,salicylic and stearic. Similarly, pharmaceutically acceptable cationsinclude, but are not limited to sodium, potassium, calcium, aluminum,lithium and ammonium. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts. Thepresent invention also encompasses prodrugs of the compounds of FormulaI.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I, Those skilled in the art will recognize varioussynthetic methodologies, which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

The compounds of this invention may contain one or more asymmetriccarbon atoms, so that the compounds can exist in differentstereoisomeric forms. These compounds can be, for example, racemates,chiral non-racemic or diastereomers. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent; chromatography,using, for example a chiral HPLC column; or derivatizing the racemicmixture with a resolving reagent to generate diastereomers, separatingthe diastereomers via chromatography or selective crystallization, andremoving the resolving agent to generate the original compound inenantiomerically enriched form. Any of the above procedures can berepeated to increase the enantiomeric purity of a compound.

When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless otherwise specified, itis intended that the compounds include the cis, trans, Z-andE-configurations. Likewise, all tautomeric forms are also intended to beincluded.

The present invention also encompasses the prodrugs of the compounds ofFormula I. Those skilled in the art will recognize various syntheticmethodologies that may be employed to prepare non-toxic pharmaceuticallyacceptable prodrugs of the compounds encompassed by Formula I. Thoseskilled in the art will recognize a wide variety of non-toxicpharmaceutically acceptable solvates, such as water, ethanol, mineraloil, vegetable oil, and dimethylsulfoxide.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes percutaneous, subcutaneous, intravascular (e.g.,intravenous), intramuscular, or intrathecal injection or infusiontechniques and the like. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula I and apharmaceutically acceptable carrier. One or more compounds of generalFormula I may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvants,and if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general Formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preservative agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques. In some cases such coatings may be prepared by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatincapsules, wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate, or kaolin,or as soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

Formulations for oral use may also be presented as lozenges.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil, orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin, or cetyl alcohol. Sweetening agents and flavoring agents maybe added to provide palatable oral preparations. These compositions maybe preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring, and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil or amineral oil or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations may also contain a demulcent, a preservative, and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono-or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds of general Formula I may also be administered in the formof suppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives, andbuffering agents can be dissolved in the vehicle.

For disorders of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical gel, spray,ointment or cream, or as a suppository, containing the activeingredients in a total amount of, for example, 0.075 to 30% w/w,preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound, which enhances absorption or penetrationof the active ingredient through the skin or other affected areas.Examples of such dermal penetration enhancers include dimethylsulfoxideand related analogs. The compounds of this invention can also beadministered by a transdermal device. Preferably topical administrationwill be accomplished using a patch either of the reservoir and porousmembrane type or of a solid matrix variety. In either case, the activeagent is delivered continuously from the reservoir or microcapsulesthrough a membrane into the active agent permeable adhesive, which is incontact with the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane. The transdermal patch may include the compound in a suitablesolvent system with an adhesive system, such as an acrylic emulsion, anda polyester patch. The oily phase of the emulsions of this invention maybe constituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier, which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase, which forms the oily, dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others. The choice of suitable oils or fats for the formulation isbased on achieving the desired cosmetic properties, since the solubilityof the active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono-or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The anti-inflammatory active ingredients are preferablypresent in such formulations in a concentration of 0.5 to 20%,advantageously 0.5 to 10% and particularly about 1.5% w/w. Fortherapeutic purposes, the active compounds of this combination inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient. The daily dose can be administered in one tofour doses per day. In the case of skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It may be convenient toformulate the animal feed and drinking water compositions so that theanimal takes in a therapeutically appropriate quantity of thecomposition along with its diet. It may also be convenient to presentthe composition as a premix for addition to the feed or drinking water.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples, whichare not to be construed as limiting the invention in scope or spirit tothe specific procedures described in them.

The starting materials and various intermediates may be obtained fromcommercial sources, prepared from commercially available compounds, orprepared using well-known synthetic methods.

The compound names in this application were created using ACD Name Proprogram, or the ChemDraw ultra program. In all cases, the given namewill enable one skilled in the art to determine the structure of thenamed compound.General Synthetic Procedures

The compounds of the instant invention may be prepared according to themethod described in Scheme 1, using methods well known in the art.

R₅ is as defined above.

Alternatively, the compounds of the instant invention may be preparedaccording to the method described in Scheme 2, using methods well knownin the art.

Q at each occurrence is independently alkyl, halogen, alkoxy,arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, CO₂H, CN,amidinooxime, NR₆R₇, NR₆R₇alkyl, —C(O)NR₆R₇ amidino, haloalkyl, orhaloalkoxy; and n is 0, 1, 2, 3, 4, or 5.

The invention is illustrated further by the following examples, whichare not to be construed as limiting the invention in scope or spirit tothe, specific procedures described in them. Those having skill in theart will recognize that the starting materials may be varied andadditional steps employed to produce compounds encompassed by theinvention, as demonstrated by the following examples. Those skilled inthe art will also recognize that it may be necessary to utilizedifferent solvents or reagents to achieve some of the abovetransformations. In some cases, protection of reactive functionalitiesmay be necessary to achieve the above transformations. In general, suchneed for protecting groups, as well as the conditions necessary toattach and remove such groups, will be apparent to those skilled in theart of organic synthesis. When a protecting group is employed,deprotection step may be required. Suitable protecting groups andmethodology for protection and deprotection such as those described inProtecting Groups in Organic Synthesis by Greene and Wuts are well knownand appreciated in the art.

Unless otherwise specified, all reagents and solvents are of standardcommercial grade and are used without further purification. Theappropriate atmosphere to run the reaction under, for example, air,nitrogen, hydrogen, argon and the like, will be apparent to thoseskilled in the art.

EXAMPLES Example 1 4-(benzyloxy)-1-(4-methylbenzyl)pyridin-2(1H)-one

4-Benzyloxy-2(1H)-pyridone (3.0 9, 0.015 mol), 4-methylbenzyl bromide(3.15 g, 0.17 mol), and potassium carbonate (3.0 g, 0.022 mol) wereheated at 80° C. for 2 hours. Contents were allowed to cool, dilutedwith water and a solid (5.52 g) was filtered. The solid wasrecrystallized from EtOAc to give colorless flakes, 2.46 g (54% yield),mp 142.8-143.3° C. FABHRMS m/z 306.1494 (M+H, C₂₀H₂₀NO₂ requires306.1494). ¹H NMR (CDCl₃/300 MHz): 7.50-7.40 (m, SH); 7.20-7.05 (m, 5H);6 07-6.00 (m, 1H); 5.95-5.90 (m, 1H); 5.05 (s, 2H); 5.00 (s, 2H); 2.32(s, 3H). Anal. Calcd for C₂₀H₁₉NO₂: C, 78.66; H, 6.27; N, 4.59. Found:C, 78.54; H, 6.38;. N, 4.58.

Example 2 4-(benzyloxy)-3-bromo-1-(4-methylbenzyl)pyridin-2(1H)-one

The material prepared in Example 1 (2.1 g, 0.007 mol) and sodium acetate(738 mg, 0.009 mol) in glacial acetic acid (15 mL) were cooled to 15° C.Bromine (0.412 mL, 0.008) in glacial acetic acid (5 mL) was addeddropwise. Contents were stirred 2 hours, coming to room temperature.Water (200 mL) was added and a light yellow solid was filtered. Thesolid was recrystallized from EtOAc to give colorless needles, 646 mg(24% yield). Mp 150.4-151.2° C. FABHRMS m/z 384.0599 (M+H, C₂₀H₁₉BrNO₂requires 384.0601). ¹H NMR (CDCl₃/300 MHz) δ: 7.42-7.30 (m, 5H);7.22-7.08 (m, SH); 6.02 (d, 1H); 5.20 (s, 2H); 5.12 (s, 2H); 2.32 (s,3H). Anal. Calcd for C₂₀H₁₈BrNO₂: C, 62.51; H, 4.72; N, 3.65. Found: C,62.11; H, 4.48; N, 3.54.

Example 3 4-(benzyloxy)-1-(4-bromobenzyl)pyridin-2(1H,)-one

The material of Example 3 was prepared according to the procedure ofExample 1. FABHRMS m/z 370.0443 (M+H, C₁₉H₁₇BrNO₂ requires 370.0428). ¹HNMR (CDCl₃/300 MHz) δ: 7.43 (d, 2H); 7.40-7.33 (m, 5H); 7.20-7.07 (m,3H); 6.04-6.01 (m, 1H); 6.00-5.92 (m, 1H); 5.03 (s, 2H); 4.98 (s, 2H).Anal. Calcd for C₁₉H₁₆BrNO₂: C, 61.64; H, 4.36; N, 3.78. Found: C,61.58; H, 4.38; N, 3.74.

Example 4 4-(benzyloxy)-3-bromo-1-(4-bromobenzyl)pyridin-2(1H)-one

The material of Example 4 was prepared according to the procedure ofExample 2. FABHRMS m/z 447.9548 (M+H, C₁₉H₁₆Br₂NO₂ requires 447.9522).¹H NMR (CDCl₃/300 MHz) δ: 7.50-7.15 (m, 10H) 6.06 (d, 1H); 5.20 (s, 2H),5.10 (s, 2H). Anal. Calcd for C₁₉H₁₅Br₂NO₂: C, 50.81; H, 3.37; N, 3,12.Found: C, 50.58; H, 3.04; N, 3.15.

Example 5. 4-(benzyloxy)-1-(4-chlorobenzyl)pyridin-2(1H)-one

The material of Example 5 was prepared according to the procedure ofExample 1. FABHRMS m/z 326.0893 (M+H, C₁₉H₁₇ClNO₂ requires 326.0948). ¹HNMR (CDCl₃/300 MHz) δ: 7.40-7.32 (m, 5H) 7.24 (AB quartet, 4H); 7.10 (d,1H); 6.03-6.00 (m, 1H); 5.98-5.92 (m, 1H) ; 5.03 (s, 2H) ; 4.99 (s, 2H)Anal. Calcd for C₁₉H₁₆ClNO₂: C, 70.05; H, 4.95; N, 4.30. Found: C,69.78; H, 4.72; N, 4.29.

Example 6 4-(benzyloxy)-3-bromo-1-(4-chlorobenzyl)pyridin-2(1H)-one

The material of Example 6 was prepared according to the procedure ofExample 2. FABHRMS m/z 404.0035 (M+H, C₁₉H₁₆BrC₁NO₂ requires 404.0053).¹H NMR (CDCl₃/300 MHz): 7.43-7.20 (m, 10OH); 6.08 (d, 1H); 5.20 (s, 2H);5.10 (s, 2H). Anal. Calcd for C₁₉H₁₅BrClNO₂: C, 56.39; H, 3.74; N, 3.46.Found: C, 56.15; H, 3.61; N, 3.35.

Example 7 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one

The material of Example 7 was prepared according to the procedure ofExample 1. FABHRMS m/z 310.1226 (M+H, C₁₉H₁₇FNO2 requires 310.1243). ¹HNMR (CDCl₃/300 MHz) δ: 7.45-7.25 (m, 5H); 7.12 (d, 1H); 7.07-6.93 (m,4H); 6.04-6.02 (m, 1H); 6.00-5.94 (m, 1H); 5.08 (s, 2H) ; 5.00 (s, 2H)Anal. Calcd for C₁₉H₁₆FNO₂: C, 73.77; H, 5.21; N, 4.53. Found: C, 73.75;H, 5.22; N, 4.58.

Example 8 4-(benzyloxy)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one

The material of Example 8 was prepared according to the procedure ofExample 2. ¹H NMR (CDCl₃/300 MHz) δ: 7.43-7.25 (m, 6H) ; 7.21 (d, 1H);7.10-6.93 (m, 3H); 6.08 (d, 1H); 5.22 (s, 2H) 5.12 (s, 2H). Anal. Calcdfor C₁₉H₁₅BrFNO₂: C, 58.78; H, 3.89; N, 3.61. Found: C, 58.79; H, 3.83;N, 3.61.

Example 9 4-(benzyloxy)-1-(2-fluorobenzyl)pyridin-2 (1H) -one

The material of Example 9 was prepared according to the procedure ofExample 1. FABHRMS m/z 310.1243 (M+H, C₁₉H_(l7)FNO₂ requires 310.1231).¹H NMR (CDCl₃/300 MHz) δ: 7.43-7.00 (m, 10H); 6.01-5.92 (m, 2H); 5.10(s, 2H); 4.99 (s, 2H). Anal. Calcd for Cl₉H₁₆FNO₂: C, 73.77; H, 5.21; N,4.53. Found: C, 73.66; H, 5.45; N, 4.46.

Example 10 4-(benzyloxy)-3-bromo-1-(2-fluorobenzyl)pyridin-2 (1H)-one

The material of Example 10 was prepared according to the procedure ofExample 2. FABHRMS m/z 388.0373 (M+H, C₁₉H₁₆FNO2 requires 388.0348). ¹HNMR (CDCl₃/300 MHz): 7.52 (d of t, 1H); 7.44-7.26 (m, 7H); 7.15-7.00 (m,2H); 6.03 (d, 1H); 5.20 (s, 2H); 5.15 (s, 2H). Anal. Calcd forC₁₉H₁₅BrFNO₂: C, 58.78; H, 3.89; N, 4.61. Found: C, 58.59; H, 4.00; N,3.57.

Example 11 4-(benzyloxy)-3-bromopyridin-2(1H)-one

The material of Example 11 was prepared according to the procedure ofExample 2. ¹H NMR (CDCl₃/300 MHz) δ: 7.50-7.30 (m, 6H); 6.20 (d, 1H);5.24 (s, 2H). Anal. Calcd for C₁₂H₁₀BrNO₂. (0.3H₂O): C, 50.48; H, 3.74;N, 4.91. Found: C, 50.79; H, 3.41; N, 4.82.

Example 124-(benzyloxy)-1-[4-(benzyloxy)benzyl]-3-bromopyridin-2(1H)-one

To the material of Example 11 (1.0 g, 0,0036 mol) in DMF (5 mL) wasadded dropwise sodium bis(trimethylsilyl)amide (1M in THF, 4 ML).Contents were stirred one hour before adding dropwise a solution of4-benzyloxybenzyl chloride (931 mg, 0.004 mol) in DMF (5 mL). Contentswere heated at 75° C. for four hours. Contents were allowed to cool andpoured into water (75 mL). A solid (1.9 g) was filtered andrecrystallized from EtOAc to give white flakes, 986 mg (57% yield). mp137.6-144.3° C. FABHRMS m/z 476.0854 (M+H, C₂₆H₂₃BrNO₃ requires476.0861). ¹H NMR (CDCl₃/300 MHz): 7.45-7.15 (m, 13H); 6.92 (d, 2H);6.01 (d, 1H); 5.20 (s, 2H); 5.08 (s, 2H); 5.03 (s, 2H). Anal. Calcd forC₂₆H₂₂BrNO₃: C, 65.55; H, 4.66; N, 2.94. Found: C, 65.54; H, 4.56; N,2.94.

Example 13 methyl 4-{[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]methyl}benzoate

The material of Example 13 was prepared according to the procedure ofExample 1. FABHRMS m/z 350.1391 (M+H, C₂₁H₂₀NO4 requires 350.1392). ¹HNMR (CDCl₃/300 MHz): 8.00 (d, 2H); 7.40-7.25 (m, 7H); 7.10 (d, 1H);6.03-6.01 (m, 1H); 6.00-5.93 (m, 1H); 5.12, (s, 2H); 5.00 (s, 2H); 3.95(s, 3H). Anal. Calcd for C₂,H₁₉NO₄: C, 72.19; H, 5.48; N, 4.01. Found:C, 72.20; H, 5.28; N, 3.97.

Example 14methyl-4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl} benzoate

The material of Example 14 was prepared according to the procedure ofExample 2. FABHRMS m/z 428.0480 (M+H, C₂₁H₁₉BrNO₄ requires 428.0497). ¹HNMR (CDCl₃/300 MHz): 8.00 (d, 2H); 7.42-7.31 (m, 7H); 7.23 (d, 1H); 6.08(d, 1H); 5.22 (d, 2H); 5.20 (s, 2H); 3.95 (s, 3H). Anal. Calcd forC₂₁H₁₈BrNO₄ (0.5 HBr, 0.5 H₂O): C, 52.80; H, 4.11; N, 2.93. Found: C,52.77; H, 4.26; N, 2.85.

Example 154-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoic acid

The material of Example 14 (1.0 g, 0.0023 mol) and 2.5N aqueous sodiumhydroxide (1.9 mL) were refluxed in methanol (10 mL) for S hours.Contents were allowed to cool and made acidic with 3N HCl to pH 2.5. Awhite solid was filtered and triturated with warm ethanol to give thedesired as a white solid (1.0 g). mp 250.8-255.7° C. FABHRMS m/z414.0360 (M+H, C₂₀H₇BrNO₄ requires 414.0341). ¹H NMR (DMSO-d₆/300 MHz):8.00-7.80 (m, 3H); 7.53-7.27 (m, 7H); 6.50 (d, 1H) ; 5.32 (s, 2H) ; 5.20(s, 2H) Anal. Calcd for C₂₀H₁₆BrNO₄: C, 57.99; H, 3.89; N, 3.38. Found:C, 57.55; H, 3.70; N, 3.36.

Example 16 4-{[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]methyl} benzonitrile

The material of Example 16 was prepared according to the procedure ofExample 1. FABHRMS m/z 317.1270 (M+H, C₂₀H₁₇N₂O₂ requires 317.1290). ¹HNMR (CDCl₃/300 MHz) δ: 7.60 (d, 2H); 7.42-7.30 (m, 7H); 7.13 (d, 1H);6.05-5.98 (m, 2H); 5.11 (S, 2H); 5.00 (s, 2H). Anal. Calcd forC₂₀H₁₆N₂O₂: C, 75.93; H, 5.10; N, 8,86. Found: C, 75.61; H, 5.07; N,8.77.

Example 174-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzonitrile

The material of Example 17 was prepared according to the procedure ofExample 2. FABHRMS m/z 395.0376 (M+H, C₂₀H₁₆BrN₂O requires 395.0395). ¹HNMR (CDCl₃/300 MHz) δ: 7.61 (d, 2H) 7,48-7.30 (m, 6H); 7.23 (d, 2H);6.12 (d, 1H); 5.22 (s, 2H); 5.20 (s, 2H). Anal. Calcd for C₂₀H₁₅BrN₂O₂:C, 60.78; H, 3.83; N, 7.09. Found: C, 60.49; H, 3.72; N, 7.02.

Example 18 4-(benzyloxy)-1-(4-tert-butylbenzyl)pyridin-2(1H)-one

The material of Example 18 was prepared according to the procedure ofExample 1. FABHRMS m/z 348.1949 (M+H, C₂₃H₂₆NO₂ requires 348.1964). ¹HNMR (CDCl/300 MHz): 7.40-7.28 (m, 7H); 7.20 (d, 2H) ; 7.10 (d, 1H) ;6.02 (d, 1H); 5.97-5.90 (m, 1H) ; 5.02 (d, 2H) ; 4.98 (d, 2H). Anal.Calcd for C₂₃H₂₅NO₂: C, 79.51; H, 7.25; N, 4.03. Found: C, 79.51; H,7.21; N, 4.08.

Example 19 4-(benzyloxy)-3-bromo-1-(4-tert-butylbenzyl)pyridin-2(1H)-one

The material of Example 19 was prepared according to the procedure ofExample 2. FABHRMS m/z 426.1023 (M+H, C₂₃H₂₅BrNO₂ requires 426.1069). 1HNMR (CDC13/300 MHz) δ: 7.43-7.20 (m, 10H); 6.02 (d, 1H); 5.20 (s, 2H);5.10 (s, 2H); 1.30 (s, 9H). Anal. Calcd for C₂₃H₂₄BrNO₂: C, 64.79; H,5.67; N, 3.29. Found: C, 64.49; H, 5.56; N, 3.19.

Example 20 4-(benzyloxy)-3-bromo-1-ethylpyridin-2(1H)-one

To 4-benzyloxy-2(1H)-pyridone (1.0 g, 0.005 mol) and potassium carbonate(1.0 g, 0.007 mol) in DMF (10 mL) was added bromoethane (0.82 mL, 0.011mol). Contents were heated at 75° C. overnight. Contents were allowed tocool and partitioned between EtOAc and water. The EtOAc layer was driedover MgSO₄, filtered, and concentrated in vacuo leaving a waxy solid,which was recrystallized from EtOAc/hexanes to give a white solid (720mg). To the white solid (700 mg, 0.003 mol) in glacial acetic acid (10mL), bromine (0.17 mL, 0.00325 mol) in glacial acetic acid (5 mL) wasadded dropwise at 15° C. Contents were stirred one hour at roomtemperature and a yellow solid (1.1 g) was filtered. The solid waspartitioned between EtOAc and 2.5N sodium hydroxide. The EtOAc layer wasdried over MgSO₄, filtered, and concentrated in vacuo leaving acolorless oil (710 mg), which solidified and was recrystallized fromEtOAc/hexanes to give the desired as a white solid (600 mg). mp61.3-64.8° C. FABHRMS m/z 310.0267 (M+H, C₁₄H₁₅BrNO₂ requires 310.0263).¹H NMR (CDCl₃/300 MHz) δ: 7.45-7.30 (m, 6H); 7.22 (dd, 1H); 6.07 (d,1H); 5.20 (s, 2H); 4.00 (q, 2H); 1.32 (t, 3H). Anal. Calcd forC₁₄H₁₄BrNO₂: C, 54.56; H, 4.58; N, 4.55. Found: C, 54.21; H, 4.38; N,4.43.

Example 21 3-bromo-4-hydroxy-1-(4-hydroxybenzyl)pyridin-2(1H)-one

The material of Example 12 (120 mg, 0.25 mmol) and 10% palladium/carbon(30 mg) in glacial acetic acid (2 mL) were shaken at 55 lbs of hydrogenfor 4 hours. Contents were filtered and the filtrate was concentrated invacuo leaving an oil, which was crystallized from EtoAc/hexanes to givethe desired as a white solid, 59 mg (80% yield), Mp 102.0-108° C.FABHRMS m/z 295.9952 (M+H, C₁₂H₁₀BrNO₃ requires 295.9922). ¹H NMR(DMSO-d₆/300 MHz) δ: 11.40 (br s, 1H); 9.40 (br s, 1H); 7.60 (d, 1H);7.10 (d, 2H); 6.70 (d, 2H); 6.02 (d, 1H); 4.93 (s, 2H). Anal. Calcd forC₁₂H₁₀BrNO₃ (1.4 H₂O): C, 44.85; H, 4.02; N, 4.36. Found: C, 45.07; H,4.10; N, 4.35.

Example 22 4-(benzyloxy)-3-bromo-1-methylpyridin-2(1H)-one hydrobromide

To 4-benzyloxy-2(1H)-pyridone (1.0 g, -0.005 mol) and potassiumcarbonate (760 mg, 0.0055 mol) in DMF (10 mL) was added methyl iodide(0.342 mL, 0.0055 mol). Contents were stirred overnight. Contents werepartitioned between EtOAc and water. The EtOAc layer was dried overMgSO₄₁ filtered, and concentrated in vacuo leaving a white solid (960mg).

To the white solid (332 mg, 0.0015 mol) in glacial acetic acid (10 mL),bromine (256 mg, 0.0016 mol) in glacial acetic acid (5 mL) was addeddropwise at 15° C. Contents were stirred one hour at room temperatureand the desired was filtered as a white solid, 262 mg (59% yield). Mp105.3-105.6° C. F-ABHRMS m/z 296.0097 (M+H, C₁₃H₁₂BrNO₂ requires296.0110). ¹H NMR (CDCl₃/300 MHz) δ: 7.45-7.30 (m, 6H); 7.22 (d, 1H);6.07 (d, 1H); 5.20 (s, 2H) ; 4.00 (q, 2H) ; 1.32 (t, 3H). Anal. Calcdfor C₁₃H₁₂BrNO₂ (HBr, 0.3H₂O): C, 41.04; H, 3.60; N, 3.68. Found: C,41.00; H, 3,87; N, 3.52.

Example 23 4-(benzyloxy)-3-bromo-1-methylpyridin-2(1H)-one

The material of Example 22 was partitioned between EtOAc and 2.5N sodiumhydroxide. The EtOAc layer was dried over MgSO₄, filtered, andconcentrated in vacuo leaving a red oil, which solidified and wasrecrystallized from EtOAc/hexanes to give the desired as colorlesscrystals (103 mg). mp 61.3-64.8° C. FABHRMS m/z 294.0112 (M+H,C₁₃H₁₃BrNO₂ requires 294.0130). ¹H NMR (CDCl₃/300 MHz) 7.45-7.30 (m, 6H); 7.22 (d, 1H) ; 6.07 (d, 1H) 5.20 (s, 2H); 4.00 (q, 2H); 1.32 (t, 3H).Anal. Calcd for C₁₃H₁₂BrNO₂: C, 53.08; H, 4.11; N, 4.76. Found: C,53.06; H, 4.20; N, 4.74.

Example 244-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}-N′-hydroxybenzenecarboximidamide

The material of Example 17 (500 mg, 0.00127 mol), hydroxylaminehydrochloride (90 mg, 0.0013 mol) and sodium bicarbonate (109 mg) wererefluxed in ethanol (15 mL) overnight. Contents were allowed to cool anda solid was filtered and washed with water to give the desired as awhite solid, 447 mg, (82% yield). mp 210.2-212.2° C. FABHRMS m/z428.0634 (M+H, C₂₀H₁₉BrN₃O₃ requires 428.0610). ¹H NMR (DMSO-d₆/300MHz): 9.66 (s, 1H); 7.98 (d, 1H); 7.65 (d, 2H); 7.55-7.35 (m, 5H); 7.30(d, 2H); 6.54 (d, 1H); 5.82 (s, 2H); 5.35 (s, 2H); 5.17 (s, 211). Anal.Calcd for C₂₀H₁₈BrN₃O₃: C, 56.09; H, 4.24; N, 9.81. Found: C, 55.92; H,4,01; N, 9.52.

Example 254-(benzyloxy)-3-bromo-1-(piperidin-4-ylmethyl)pyridin-2(1H)-onehydrochloride

To the material of Example 11 (924 mg, 0.0033 mol) in DMF (5 mL) wasadded dropwise sodium bis(trimethylsilyl)amide (1M in THF, 3.6 mL).Contents were stirred one hour before adding dropwise a solution of4-methanesulfonyloxymethyl-1-piperidine-1-carboxylic acid tert-butylester (J. Labelled Compd, Radiopharm, 38(7), 1996, 595-606) (1.0 g,0.0036 mol) in DMF (5 mL). Contents were heated at 75° C. overnight.Contents were allowed to cool and poured into water (100 mL). A solidwas filtered and recrystallized from EtOAc to give white crystals (546mg). The white crystals were refluxed in 4 N HCl/dioxane (10 mL) for 3hours, allowed to cool and filtered to give the desired as a whitesolid, 415 mg (30% yield). mp 207.9° C. FABHRMS m/z 377.0852 (M+H,C₁₈H₂₃BrClN₂O₂ requires 377.0865). ¹H NMR (DMSO-d₆/300 MHz) δ: 8.90 (br,1H); 8. 64. (br, 1H); 7.80 (d, 1H); 7. 50-7.30 (m, 5H); 6.48 (d, 1H);5.30 (s, 2H) ; 3.83 (d, 2H) ; 3.20 (d, 2H); 2.88-2.64 (m, 2H); 2.10-1.90(m, 1H); 1.60 (d, 2H) ; 1.50-1.40 (m, 2H). Anal. Calcd forC₁₈H₂₂BrClN₂O₂ (0.3. H20): C, 51.58; H, 5.43; N, 6.68. Found: C, 51.59;H, 5.42; N, 6.81.

Example 26 4-(benzyloxy)-1-(4-(trifluoromethyl)benzyl]pyridin-2(1H)-one

The material of Example 26 was prepared according to the procedure ofExample 1. FABHRMS m/z 360.1213 (M+H, C₂₀H₁₇F₃NO₂ requires 360.1211). ¹HNMR (CDCl₃/300 MHz) δ: 7.60 (d, 21H) 7.41-7.30 (m, 7H); 7.13 (d, 1H);6.05-6.01 (m, 1H); 6.00-5.95 (m, 1H); 5.13 (s, 2H) ; 5.00 (s, 2H) Anal.Calcd for C₂₀H₁₆F₃NO₂: C, 66.85; H, 4.49; N, 3.90. Found: C, 66.64; H,4.26; N, 3.93.

Example 27 4-(benzyloxy)-3-bromo-1-[4-(trifluoromethyl) benzyl]pyridin-2(1H) -one

The material of Example 27 was prepared according to the procedure ofExample 2, FABHRMS m/z 438.0308 (M+H, C₂₀H₁₆BrF₃NO₂ requires 438.0316).¹H NMR (CDCl₃/300 MHz) δ: 7.65-7.20 (m, 10H); 6.13-6.03 (m, 1H);5.30-5.13 (m, 4H). Anal. Calcd for C₂₀H₁₅BrF₃NO₂: C, 54.81; H, 3.45; N,3.20. Found: C, 54.69; H, 3,34; N, 3.19.

Example 284-(benzyloxy)-3-bromo-1-(piperidin-3-ylmethyl)pyridin-2(1H)-onehydrochloride

To the material of Example 11 (3.1 g, 0.011 mol) in DMF (20 mL) wasadded dropwise sodium bis(trimethylsilyl)amide (1M in THF, 12 mL).Contents were stirred one hour before adding dropwise a solution of3-methanesulfonyloxymethyl-1-piperidine-1-carboxylic acid tert-butylester (Bioorg. Med. Chem. Lett, 8(13), 1998, 1595-1600) (4.2 g, 0.015mol) in DMF (5 mL). Contents were heated at 75° C. overnight. Contentswere allowed to cool, poured into water (100 mL) and a solid wasfiltered. The solid was stirred in 4 N HC1/dioxane (15 mL) for 3 hoursand filtered to give the desired as a white solid, 752 mg (18% yield).mp 138.1-139.2° C. FABHRMS m/z 377.0859 (M+H, C₁₈H₂₂BrN₂O₂ requires377.0865). ¹H NMR (DMSO-d₆/300 MHz): 9.50-9.10 (br, 2H); 8.00 (d, 1H);7.50-7.30 (m, 5H); 6.93 (d, 1H); 5.30 (s, 2H); 4.30-3.90 (m, 3H);3.40-3.10 (m, 3H); 2.80-2.50 (m, 3H); 2.40-2.00 (m, 1H); 1.90-1.60 (m,4H); 1.40-1.10 (m, 1H). Anal. Calcd for C₁₈H₂,BrN₂O₂ (2HC1, 0.25 H20) C,47.-55; H, 5.21; N, 6.16. Found: C, 47.48; H, 5.46; N, 6.27.

Example 29 4-(benzyloxy)-3-bromo-1-(2-thien-3-ylethyl)pyridin-2(1H)-one

To the material of Example 11 (500 mg, 0.0018 mol) in DMF (5 mL) wasadded dropwise sodium bis(trimethylsilyl)amide (1M in THF, 2 mL).Contents were stirred one hour before adding dropwise a solution ofmethanesulfonic acid 2-thiophen-3-yl-ethyl ester (J.A.C.S, 109(6), 1987,1858-1859) (412 mg, 0.002 mol) in DMF (5 mL). Contents were heated at75° C. overnight. Contents were allowed to cool, poured into water (100mL), and extracted into EtOAc, dried over MgSO₄, filtered, andconcentrated in vacuo leaving a light yellow oil. The oil was purifiedby silica gel chromatography eluting with 50% EtOAc/hexanes to give thedesired as a white solid, 199 mg (28% yield). mp 134.0-134.3° C.

FABHRMS m/z 390.0144 (M+H, C₁₈H₁₇BrNO₂S requires 390.0163). ¹H NMR(CDCl₃/300 MHz) 7.43-7.20 (m, 6H) ; 6.92-6.80 (m, 3H) 5.90 (d, 1H); 5.20(s, 2H); 4.13 (t, 2H); 3.10 (t, 2H). Anal. Calcd for C₁₈H₁₆BrNO₂S: C,55.39; H, 4.13; N, 3.59. Found: C, 55.21; H, 3.87; N, 3.52.

Example 30 4-(benzyloxy)-3-bromo-1-(2-thien-2-ylethyl)pyridin-2(1H)-one

To the material of Example 11 (1.0 g, 0.0036 mol) in DMF (10 mL) wasadded dropwise sodium bis(trimethylsilyl)amide (1M in THF, 4 mL).Contents were stirred one hour before adding dropwise a solution ofmethanesulfonic acid 2-thiophen-2-yl-ethyl ester (J. Chem. Res. . . .Miniprint, 6, 2000, 701-715) (824 mg, 0.004 mol) in DMF (5 mL). Contentswere heated at 75° C. overnight. Contents were allowed to cool, pouredinto water (100 mL), and filtered a solid. The solid was recrystallizedfrom EtOAc to give the desired as a white solid, 411 mg (29% yield). mp128.0-129.5° C. FABHRMS m/z 390.0160 (M+H, C₁₈H₁₇BrNO₂S requires390.0163). 1H NMR (CDCl₃/300 MHz).6: 7.48-7.30 (m, 5H); 7.12. (d, 1H);6.95-6.80 (m, 2H); 6.75-6.68 (m 1H); 5.95 (d, 1H); 5.20 (s, 2H); 4.16(t, 2H) ; 3.30 (t, 2H) Anal. Calcd for C₁₈H₁₆BrNO₂S: C, 55.39; H, 4.13;N, 3.59. Found: C, 55.06; H, 4.01; N, 3.56.

Example 31 4-(benzyloxy)-3-bromo-1-[3-(trifluoromethyl)benzyl]pyridin-2(1H)-one

To the material of Example 11 (500 mg, 0.0018 mol) in DMF (5 mL) wasadded dropwise sodium bis(trimethylsilyl)amide (1M in THF, 2 mL).Contents were stirred one hour before adding dropwise a solution of3-trifluoromethylbenzyl bromide (478 mg, 0.002 mol) in DMF (5 mL).Contents were heated at 750C for 2 hours. Contents were allowed to cool,poured into water (100 mL), and extracted with EtOAc, which was driedover MgSO₄, filtered, and concentrated in vacuo leaving a white solid.The solid was recrystallized from EtOAc to give the desired as a whitesolid, 341 mg (43% yield). mp 181.5-181.6° C. FABHRMS m/z 438.0301 (M+H,C₂₀H₁₆BrF₃NO₂ requires 438.0316). ¹H NMR (CDCl₃/300 MHz): 7.60-7.20 (m,10H) ; 6.10 (d, 1H) ; 5.14 (s, 2H) ; 5.20 (s, 2H). Anal. Calcd forC₂₀H₁₅BrF₃NO₂: C, 54.81; H, 3.45; N, 3.20. Found: C, 54.81; H, 3.36; N,3.13.

Example 32 4-(benzyloxy)-3-bromo-1-[2-(trifluoromethyl)benzyl]pyridin-2(1H)-one

The material of Example 32 was prepared according to the procedure ofExample 31.

FABHRMS m/z 438.0280 (M+H, C₂₀H₁₆BrF₃NO₂ requires 438.0316). ¹H NMR(CDCl₃/300 MHz) δ: 7.68 (d, 1H); 7.55-7.20 (m, 8H); 7.15 (d, 1H); 6.10(d, 1H), 5.40 (s, 2H); 5.13 (s, 2H). Anal. Calcd for C₂₀H₁₅BrF₃NO₂: C,54.81; H, 3.45; N, 3.20. Found: C, 54.48; H, 3.36; N, 3.17.

Example 33 4-(benzyloxy)-1-[4-(trifluoromethoxy)benzyl]pyridin-2(1H)-one

The material of Example 33 was prepared according to the procedure ofExample 1.

FABHRMS m/z 376.1158 (M+H, C₂₀H₁₇F₃NO₃ requires 376.1161). 1H NMR(CDCl₃/300 MHz) δ: 7.40-7.05 (m, 10H); 6.05-5.95 (m, 2H); 5.06 (s, 2H);4.98 (s, 2H). Anal. Calcd for C₂₀H₁₆F₃NO₃: C, 64.00; H, 4.30; N, 3.73.Found: C, 63.97; H, 4.26; N, 3.57.

Example 34 4-(benzyloxy)-3-bromo-1-[4-(trifluoromethoxy)benzyl]pyridin-2(1H)-one

The material of Example 34 was prepared according to the procedure ofExample 2.

FABHRMS m/z 454.0240 (M+H, C₂₀H₁₆BrF₃NO₃ requires 454.0266). ¹H NMR(CDCl₃/300 MHz) δ: 7.45-7.10 (m, 10H); 6.08 (d, 1H); 5.20 (s, 2H) ; 5.12(s, 2H). Anal. Calcd for C₂₀H₁₅BrF₃NO₃: C, 52.88; H, 3.33; N, 3.08.Found: C, 52.53;,H, 3.09; N, 2.92.

Example 35 1-benzyl-4-(benzyloxy)-6-methylpyridin-2(1H)-one

Step 1: Preparation of 1-Benzyl-4-hydroxy-6-methylpyridin-2 (1H) -one.

4-hydroxy-6-methyl-2-pyrone (0.2 mol, 25.2 g) and benzylamine (0.2 mol,21.4 g) were added to water (800 mL) and heated to reflux with stirringfor 2 hours. After cooling to room temperature, a light brown solid wascollected by filtration. (33.4 g, 77%): ¹H NMR (DMSO-d₆/300 MHz) δ: 10.5(s, 1H), 7.4-7.1 (m, 5H), 5.8-5.6 (m, 2H), 5.2 (s,2H), 5.1 (s, 2H), 2.2(s, 3H). ESHRMS m/z 216.100 (M+H, C₁₂H₁₃NO₂ requires 216.102).

Step 2: Preparation of 1-benzyl-4-(benzyloxy)-6-methylpyridin-2(1H)-one.

1-benzyl-4-hydroxy-6-methylpyridin-2(1H)-one (10 mmol, 2.15 g),dichloromethane (100 mL), benzylbromide (11 mmol, 1.88 g), sodiumhydroxide (2.5 N, 20 mmol, 8 ML), and benzyltriethylammonium chloride(0.5 g) were vigorously stirred at room temperature for 16h.Hydrochloric acid (1 N) was added until the mixture produced an acidicreaction to pH paper. The mixture was then extracted with ethyl acetate(3×50 mL). The combined organic extracts were washed with brine, driedover magnesium sulfate, filtered, and concentrated. The product wasobtained by flash chromatography eluting with ethyl acetate:hexanes(1:2). The appropriate fractions were concentrated to a clear oil. (1.3g, 43%): ¹H NMR (DMSO-d₆/300 MHz) δ: 7.4-7.1 (m, 10 H), 6.0-5.9 (m, 2H),5.2 (s,2H), 5.1 (s, 2H), 2.2 (s, 3H) ESHRMS m/z 306.147 (M+H, C₂₀H₁₉NO₂requires 306.149).

Example 36 1-benzyl-4-(benzyloxy)-3-bromo-6-methylpyridin-2(1H)-one

The product from example 35,1-benzyl-4-(benzyloxy)-6-methylpyridin-2(1H)-one (4.2 mmol, 1.3 g),acetic acid (50 mL), and sodium acetate (5.0 mmol, 0.41 g) were stirredat room temperature. Bromine (4.2 mmol, 0.67 g) was added drop wise withstirring. After M hour, water (100 mL) was added and the mixture wasextracted with ethyl acetate (3×50 mL). The combined organic extractswere washed with saturated aqueous sodium bicarbonate solution andbrine. After drying over magnesium sulfate and concentrating, themixture was purified by flash column chromatography eluting with ethylacetate:hexanes (1:2). The appropriate fractions were concentrated toyield a light oil. (1.0 g, 629): ¹H NMR (DMSO-d₆/300 MHz) 7.4-7.0 (m, 10H), 6.5 (s, 1H), 5.29 (s,21), 5.27 (s, 2H), 2.2 (s, 3H). ESHRMS m/z384.057 (M+H, C₂₀H₁₈BNO₂Br requires 384.060).

Example 37 1-benzyl-4-(benzyloxy)-3,5-dibromo-6-methylpyridin-2(1H)-one

The product from example 35,1-benzyl-4-(benzyloxy)-6-methylpyridin-2(1H)-one (4.2 mmol, 1.3 g),acetic acid (50 ML), and sodium acetate (5.0 mmol, 0.41 g) were stirredat room temperature. Bromine (4.2 mmol, 0.67 g) was added drop wise withstirring. After ½ hour, water (100 mL) was added and the mixture wasextracted with ethyl acetate (3×50 mL). The combined organics werewashed with saturated aqueous sodium bicarbonate solution and brine.After drying over magnesium sulfate and concentrating, the mixture waspurified by flash column chromatography eluting with ethylacetate:hexanes (1:2). The appropriate fractions were concentrated toyield a white solid. (0.3 g, 15%): 1H NMR (DMSO-d₆/300 MHz) 7.5-7.0 (m,10 H), 5.42 (s,2H), 5.07 (s, 2H), 2.45 (s, 3H). ESHRMS m/z 463.966 (M+H,C₂₀H₁₇NO₂Br₂ requires 463.968).

Example 38 1-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one

Step 1: Preparation of 1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl4-bromobenzenesulfonate.

1-benzyl-4-hydroxy-6-methylpyridin-2(1H)-one (from example 35) (10 mmol,2.15 g), N,N′-dimethylformamide (30 mL), potassium carbonate (20 mmol,2.76 g), and 4-bromobenzenesulfonyl chloride (10 mmol, 2.55 g) werestirred at room temperature for 16 hours. Hydrochloric acid (IN) wasadded until the mixture was acidic to pH paper. Brine (50 mL) was addedand the mixture extracted with ethyl acetate (3×50 mL). The combinedorganic extracts were washed with brine and dried over magnesiumsulfate, and filtered. After concentrating, the material was purified byflash column chromatography eluting with ethyl acetate:hexanes (1:2).The appropriate fractions were concentrated to a clear oil, whichsolidified upon standing several days to a white solid. (3.3 g, 76%): 1HNMR (DMSO-d₆/400 MHz) 7.9 (m, 4H), 7.32-7.00 (m, 5H), 7.3 (m, 1H), 6.12(d, J=2.4 Hz, 1H), 6.02 (d, J=2.8 Hz, 1H), 5.20 (s, 2H), 2.2 (s, 3H).ESHRMS m/z 436.002 (M+H, C₁₉H₁₆NO₄SBr requires 436.004).

Step 2: Preparation of1-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one.

1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl 4-bromobenzenesulfonate(3.0 mmol, 1.3 g), N,N′-dimethylformamide (30 mL), 3-chlorobenzylalcohol (3.0 mmol, 0.43 g), and sodium hydroxide (60%, 3.3 mmol, 0.13 g)were stirred at room temperature under nitrogen for 4 hours.Hydrochloric acid (1 N, 10 mL) was added and the mixture extracted withethyl acetate (3×25 mL). The combined organic extracts were washed withsaturated aqueous sodium bicarbonate solution and brine. After dryingover magnesium sulfate and concentrating, the mixture was purified byflash column chromatography eluting with ethyl acetate:hexanes (1:1) toobtain a light yellow oil. (14.3 g, 64%): 1H NMR (DMSO-d₆/300 MHz) δ:7.4-7.0 (m, 10 H), 6.0-5.8 (m, 2H), 5.2 (s,2H), 5.0 (s, 2H), 2.1 (s,3H). ESERMS m/z 340.110 (M+H, C₂₀H₁₈NO₂Cl requires 340.110).

Example 391-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one

The product of example 38 (SC-83316),1-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.91 mmol,310 Mg), acetic acid (20 mL), and sodium acetate (0.91 mmol, 80 Mg) werestirred at room temperature when bromine (0.91 mmol, 145 Mg) was added.After stirring for one hour, the mixture was concentrated, dissolved inethyl acetate, and washed successively with saturated aqueous sodiumbicarbonate solution, brine, and water. After drying over magnesiumsulfate and concentrating, the product was recrystallized fromtetrahydrofuran/hexanes to yield a white solid. (240 Mg, 63%) ¹H NMR(DMSO-d₆/300 MHz) 7.6-7.0 (m, 10 H), 6.5 (s, 1H), 5.33 (s,2H), 5.33 (so2H), 2.3 (s, 3H). ESHRMS m/z 420.019 (M+H, C₂₀H₁₇NO₂BrCl requires420.019).

Example 40 1-Benzyl-4-[2,6-(dichlorobenzyl)oxy]pyridin-2(1H)-one

Step 1. Preparation of 4-[(2,6-dichlororbenzyl) oxy]pyridine-1-oxide.

2,6-Dichlorobenzyl alcohol (12.57 g, 71 mmol) was dissolved in DMF, (100mL). Sodium hydride (2.84 g, 71 mmol, of a 60% dispersion in mineraloil) was added in portions. Reaction mixture stirred for one hour.4-Nitropyridine-1-oxide (10.0 g, 71 mmol) dissolved in DMF (150 mL) wasadded via cannula. Reaction stirred at room temperature for 16 hours.The solvent was evaporated, and the residue was purified by flash columnchromatography (dichloromethane-methanol, 10:1) to yield an orange oil.Addition of ethyl acetate caused the formation of a yellow precipitate13.5 g (70%).

Step 2. Preparation of 4-[(2,6-dichlorobenzyl)oxy]pyridine 1-oxide.

4-[(2,6-Dichlororbenzyl)oxy]pyridine-1-oxide (Step 1) (4.0 g, 14.8 mmol)was dissolved in acetic anhydride (30 mL). The reaction mixture washeated at reflux for 6 hours. Stirred at room temperature for 16 hours.The solvent was evaporated, and the residue was dissolved indichloromethane (50 mL). Extracted with 2,5 N NaOH (2×25 mL), and H₂O(25 mL). The organic phase was dried over MgSO₄, filtered, andevaporated to yield a brown solid. Recrystallized from hot ethylacetate. Obtained a tan solid (0.984 g, 25%).

Step 3. Preparation of1-benzyl-4-[2,6-(dichlorobenzyl)oxy]pyridin-2(1H)-one.

4-[(2,6-Dichlorobenzyl)oxy]pyridine 1-oxide (0.500 g, 1.85 mmol) wasdissolved in DMF (20 mL). Potassium carbonate (0.511 g, 3.70 mmol) wasadded, followed by benzyl bromide (0.260mL, 0.400 g, 2.20 mmol). Thereaction mixture was stirred at room temperature for 16 hours. Solventwas evaporated, and the residue dissolved in ethyl acetate (S0 mL).Extracted with H₂O (2×25 mL), and brine (25 mL). The organic phase wasdried over MgSO₄, filtered, and evaporated to yield a tan solid.Recrystallized from ethyl acetate/hexane. Filtered a light tan solid(0.502 g, 75%). mp 151.6-152.0° C. ¹H NMR (CDCl₃/300 MHz) δ: 7.31 (m,8H), 7.12 (d, 1H, J=7.45 Hz), 6.13 (d, 1H, J=2.42 Hz), 5.90 (dd, 1H,J=2.62 Hz), 5.22 (s, 2H), 5.10 (s, 2H) ESHRMS m/z 360.0551 (M+HC₁₉H₁₅Cl₂NO₂ requires 360.0558).

Example 4611-Benzyl-3-bromo-4-[2,6-(dichlorobenzyl)oxy]pyridin-2(1H)-one

1-Benzyl-4-[2,6-(dichlorobenzyl)oxy]pyridin-2(1H)-one (0.400 g, 1.11mmol) was dissolved in acetic acid (10 mL). Sodium acetate (0.091 g,1.11 mmol was added, and the mixture was cooled to 15° C. Bromine (0.195g, 1.22 mmol) was added via syringe. The reaction stirred at roomtemperature for 2 hours. Water (15 mL) was added, and the mixturetransferred to a separatory funnel. Ethyl acetate (50 mL) was added andthe layers were separated. The organic phase was washed with aqueousNaHCO₃ (2×25 mL), dried over MgSO₄, filtered, and evaporated to yield awhite solid. Recrystallization from ethyl acetate/hexanes afforded awhite solid (0.380 g, 62%). mp 156.3-157.9° C. ¹HNMR (CDCl₃/300 MHz) δ:7.34 (m, 9H), 6.24 (d, 1H, J=7.65 Hz), 5.37 (s, 2H), 5.18 (s, 2H).ESHRMS m/z 439.9646 (M+H C₁₉H₁₄BrCl₂NO₂ requires 439.9641).

Example 42 1-Benzyl-4-[(2-chlorobenzyl)oxy]pyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed in Example 1. mp 124.6-125.0° C. ¹HNMR (CDCl₃/300 MHz) δ: 7.36(m, 9H), 7.14 (d, 1H, J=7.65 Hz), 6.04 (d, 1H, J=2.62 Hz), 5.98 (d, 1H,J=2.82 Hz), 5.10 (s, 2H), 5.09 (s, 2H). ESHRMS m/z 326.0950 (M+HC₁₉H₁₆ClNO₂ requires 326.0948). Anal. Calc'd. for C₁₉H₁₆ClNO₂: C, 70.05;H, 4.95; N, 4.30; Cl, 10.88. Found: C, 69.87; H, 4.74; N, 4.42, Cl,11.08.

Example 43 1-Benzyl-3-bromo-4-[(2-chlorobenzyl)oxy]pyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed in Example 2. mp 143.3-145.5° C. ¹HNMR (CDCl₃/300 MHz) δ: 7.63(d, 2H, J=1.81 Hz), 7.44 (m, 9H), 6.06 (d, 1H, J=7.65 Hz), 5.29 (s, 2H),5.17 (s, 2H). ESHRMS M/z 406.0036 (M+H C₁₉H₁₅BrClNO₂ requires 406.0032).Anal. Calc'd. for C₁₉H₁₅Cl BrNO₂: C, 56.39; H, 3.74; N, 3.46; Cl, 8.76.Found: C, 56.01; H, 3.38; N, 3.36, Cl, 9.01.

Example 44 1-Benzyl-3-bromo-4-[(4-methylbenzyl)oxy]pyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed in Example 2. mp 149.0-149.7° C. ¹HNMR (CDCl₃/300 MHz) δ: 7.25(m, 1OH), 6.04 (d, 1H, J=7.65 Hz), 5.17 (s, 2H), 5.15 (s, 2H), 2.34 (s,3H). ESHRMS m/z 386.0583 (M+H C₂₀H₁₈BrNO₂ requires 386.0581).

Example 45 1-Benzyl-4-[(3-chlorobenzyl)oxy]pyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed in Example 1. mp 95.5-95.7° C. ¹HNMR (CDCl₃/300 MHz) δ: 7.34(m, 9H), 7.13 (d, 1H, J=7.45 Hz), 5.96 (m, 1H), 5.95 (d, 1H, J=7.45 Hz),5.09 (s, 2H), 4.96 (s, 2H). ESHRMS m/z 326.0977 (M+H C₁₉H₁₆ClNO₂requires 326.0948).

Example 46 1-Benzyl-4-[benzylthiol-3-bromopyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed in Example 2. mp 180.6-182.1° C. ¹HNMR (CDCl₃/300 MHz) δ: 7.33(m, 10H), 7.14 (d, 1H, J=7.45 Hz), 6.08 (d, 1H, J=7.45 Hz), 5.13 (s,2H), 4.15 (s, 2H). ESHRMS m/z 386.0211 (M+H C₁₉H₁₆BrNOS requires386.0214).

Example 47

1-Benzyl-3-bromo-4-{[2-(trifluoromethyl)benzyl]oxy}pyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed in Example 2. mp 133.2-133.5° C. ¹HNMR (CDCl₃/300 MHz) δ: 7.81(d, 1H, J=7.65 Hz), 7.68 (d, 1H, J=7.65 Hz), 7.61 (t, 1H, J=7.65 Hz),7.38 (m, 7H), 6.01 (d, 1H, J=7.85 Hz), 5.39 (s, 2H), 5.16 (s, 2H).ESHRMS m/z 438.0313 (M+H C₂₀H₁₅BrF₃NO₂ requires 403.0316).

Example 48 1-Benzyl-4-(benzyloxy)-3-iodopyridin-2(1H)-one

A mixture of N,O-dibenzyl-2-pyridone (2.0 g, 6.87 mmol)N-iodosuccinimide (1.7 g), dichloroacetic acid (0.15 mL) in acetonitrile(40.0 mL) was heated at 65° C. under argon atmosphere is for 3.5 h, withconstant stirring. The reaction mixture was concentrated to dryness, andthe residue was purified by silica gel flash chromatography usingEtOAc/hexanes 1:1 v/v to give the title compound 2.3 g (80%) as a flakywhite solid: ¹H—NMR (CDCl₃) δ: 7.4-7.2 (m, 10 H), 7.19 (1H, d, J=7.6Hz), 5.95 (d, 1H, J=7.6 Hz), 5.2 (s, 1H) 5.15 (s, 2H) ; ER-MS m/z=418(MH ⁺) ; HR-MS m/z calcd C₁₉H₁₇NO₂ 418.0304, found 418.0277.

Example 49 1-benzyl-4-(benzyloxy)-3-vinylpyridin-2(1H)-one

A solution of 1-benzyl-4-(benzyloxy)-3-iodopyridin-2(1H)-one (1.9 g,4.56 mmol) and vinyl-tri-butyltin (2.5 mL) in acetonitrile (20 0 mL)containing DMF (2.0 mL) was degassed using house vacuum and purged withargon. Then added PdCl₂(PPh₃)₂ (0.3 g) and the mixture was heated at 65°C. under argon atmosphere for 4 h, with stirring. The solvents weredistilled in vacua, and the residue was triturated with EtOAc andfiltered through a pad of celite. The filtrate was concentrated and theresidue was purified by silica gel flash chromatography using 25% EtOAcin hexanes to give the title compound (0.75 g. 50%) as an orange coloredsolid.

¹H—NMR (CDCl₃) δ: 7.4-7.2 (m, 10 H), 7.14 (d, 1H, J=7.6 Hz), 7.05 (dd,1H, J=12.0 Hz), 6.47 (dd, 1H, J=2.8 Hz), 6. 07 (d, 1H, J=7.6 Hz), 5.4(dd, 1H, J=2.8 Hz), 5.13 (s, 4H); ER-MS m/z=418 (MH⁺); ER-MS m/z 318(MH⁺); HR-MS m/z calcd C₂₁H₂₀NO₂ 318.1494, found 318.1480.

Example 50 1-benzyl-4-(benzyloxy)-3-ethylpyridin-2(1H)-one

To a solution of 1-benzyl-4-(benzyloxy)-3-vinylpyridin-2(1H)-one (0.5 g,1.6 mmol) in EtOH (10.0 mL) and EtOAc (10.0 mL) was added Pd/C (10%,0.25 g) and stirred in an atmosphere of hydrogen gas at 30 psi for 16 h.The catalyst was removed by filtration, the filtrate was concentrated todryness and the resulting residue was purified by silica gel flashchromatography using EtOAc/hexanes (1:1, v/v) to afford the titlecompound (0.32 g, 64%) as a pale yellow powder: ¹H—NMR (CD₃OD) δ: 7.52(d, 1H, J=7.6 Hz), 7.39-7.2 (m, 10 H), 6.41 (d, 1H, J=7.6 Hz), 5.18 (s,2H), 5.15 (s, 2H), 2.58 (q, 2H, J=7.2 Hz), 1.03 (t, 3H, J=7.2 Hz), ER-MSm/z=320 (MH⁺); HR-MS m/z calcd C₂₁H₂₂NO₂ 320.1651, found 320.1648.

Example 51 3-acetyl-4-(benzyloxy)-1-(2-chlorophenyl)-6-methylpyridin-2(11H)-one

Step A

Preparation of3-acetyl-1-(2-chlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

A mixture of 2-chlorophenylisocyanate (3.0 g, 19.53 mmol), and diketene(3.3 g, 39.28 mmol) in toluene (10.0 mL) containing triethylamine (0.05mL) was heated to reflux for 6 h, under an atmosphere of argon. Toluenewas distilled in vacuo and the resulting residue was purified by silicagel flash chromatography using 25% EtOAc in hexanes as the eluent toafford the title compound (0.85 g, see ref: Heterocycles 27 (9), 2063,1988.) as a pale yellow solid: ¹H—NMR (CD₃OD) δ: 7.63 (m, 1H), 7.52 (m,2H), 7.4 (m, 1H), 6.14 (s, 1H), 2.58 (s, 3H), and 1.95 (s, 3H); ES-MSm/z=278 (MH⁺).

Step B

Preparation of3-acetyl-4-(benzyloxy)-1-(2-chlorophenyl)-6-methylpyridin-2(1H)-one

To a solution of3-acetyl-1-(2-chlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.56 g,2.02 mmol) in DMF (5.0 mL), benzyl bromide (0.3 mL) and potassiumcarbonate. (0.3 g, 2.16 mmol) were added. The mixture was stirred atroom temperature for 3 h, and at 65° C. for 1 h under argon atmosphere.The reaction mixture was concentrated in vacuo and the residue waspartitioned between 5% citric acid (25 mL) and EtOAc (50.0 mL) Theorganic phase was washed with brine, dried (Na₂SO₄), filtered, andconcentrated to dryness. The resulting residue was purified by silicagel flash chromatography using 50% EtOAc in hexanes to afford the titlecompound (0.58 g, 75%) as a pale yellow amorphous substance: ¹H—NMR(CD₃OD) δ: 7.65-7.3 (m, 9H), 6.5 (s, 1H), 5.31 (s, 2H), 2.42 (s, 3H),and 2.01 (s, 3H); ER-MS m/z=368 (MH⁺); HR-MS m/z calcd C₂₁H₁₉NO₃Cl368.1060, found 368.1053.

Example 52 1-benzyl-3-bromo-4-(2-phenylethyl)pyridin-2(1H)-one

Step A

Preparation of 1-Benzyl-3-bromo-4-hydroxypyridin-2(1H)-one

A suspension of N-benzyl-4-hydroxy-2-pyridone ((0.75 g, 3.7 mmol), NBS(0.7 g, 1.05 mmol) in dichloromethane was stirred at room temperaturefor 1.5 h under argon atmosphere. It was diluted with dichloromethane(25 mL), cooled and filtered. The solids were washed withdichloromethane and dried in vacuo. The filtrate and the washings werecombined and washed with water, dried (Na₂SO₄), filtered, andconcentrated to dryness. The resulting residue was washed with EtOAc,and dried in vacuo to give a combined mass of 0.65 g of the titlecompound as a white powder: ¹H NMR (CD₃OD) δ: 7.54 (d, 1H, J=7.6 Hz),7.27 (m, 5H), 6.12 (d, 1H, J=7.6 Hz), 5.15 (s, 2H); ES-MS: m/z=280(MH⁺).

Step B

Preparation of 1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate

To a cold (−30° C.) suspension of1-benzyl-3-bromo-4-hydroxypyridin-2(1H)-one (0.78 g, 2.8 mmol) indichloromethane (10.0 mL), was added triethylamine (0.6 mL, 4.28 mmol ),followed by the addition of triflic anhydride (0.7 mL, 4.17 mmol). Theresulting mixture was stirred at −30° C. under argon atmosphere for 1 h.The reaction mixture was then poured into ice/water mixture (50 mL) andthe products were extracted with dichloromethane (2×25 mL). The combinedorganic extracts were washed with water (2×20 mL), dried (Na₂SO₄),filtered, and concentrated to dryness. The residue was dried in vacuo toafford the desired trifluorosulfonate (1.0 g) as a pale yellow solidwhich used as such in the next step: ¹H—NMR (CDCl₃) δ: 7.35 (m, 6H),6.26 (d, 1H, J=8.0 Hz); ¹⁹F—NMR (CDCl₃) δ: −73.73 ppm; ES-MS: m/z=412(MH⁺).

Step C

Preparation of 1-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(1H)-one.

To a solution of 1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate (1.0 g) in DMF (5.0 mL) was addedphenylacetylene (0.4 mL) and degassed using house vacuum. The reactionflask was then purged with argon, added diisopropylethylamine (0.53 mL),and PdCl₂(PPh₃)₂ (0.35 g) were added. The resulting mixture was stirredat room temperature for 15 min and heated at 65° C. under an argonatmosphere for 3h. The dark colored reaction mixture was concentrated invacuo, and the residue was partitioned between EtOAc (50 mL) and 5%aqueous citric acid (25 mL). The organic extracts were washed withwater, dried (Na₂SO₄), filtered, and concentrated to dryness. Theresulting material was purified by silica gel flash chromatography using25% EtOAc in hexanes as the eluent. The appropriate fractions werecombined, concentrated under reduced pressure, and the residue wascrystallized from EtoAc/hexanes to afford the title compound (0.35 g) asshiny flakes: ¹H NMR (CDCl₃) δ: 7.57 (m, 2H), 7.38 (m, 8H), 7.21 (d, 1H,J=6.8 Hz), 6.25 (d, 1H, J 6.8 Hz), and 5.16 (d, 2H), ES-MS: m/z=364(MH⁺); HR-MS m/z (MH⁺) calcd C₂₀H₁₅NOBr 364.0337, found 364.0337.

Step D

Preparation of 1-benzyl-3-bromo-4-(2-phenylethyl)pyridin-2(1H)-one.

A mixture of 1-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(1H)-one (0.3g), and platinum oxide (0.05 g) in a solvent mixture of EtOAc (10.0 mL)and EtOH (10.0 mL) was stirred in an atmosphere of hydrogen at 15 psi ina Fischer porter bottle for 45 min. The catalyst was removed byfiltration, and filtrate was concentrated. The resulting residue waspurified by silica gel flash chromatography using 25% EtOAc in hexanesas the eluent. The appropriate fractions (visualized under an UV lamp)were combined and concentrated under reduced pressure. The resultingresidue was crystallized from EtOAc/hexanes to give the title compound(0.16 g) as shiny flakes: 1H—NMR (CD₃OD) δ: 7.56 (d, 1H, J=6.8 Hz),7.31-7.17 (m, 10 H), 6.24 (d, 1H, J=6.8 Hz), 5.19 (s, 2H), 2.96 (m, 2H),and 2.91 (m, 2H); ES-MS m/z=368 (MH⁺); HR-MS m/z (MH⁺) calcd C₂₀H₁₉NOBr368.0650, found 368.0630.

Example 533-bromo-1-(3-fluorobenzyl)-6-methyl-4-(2-phenylethyl)pyridin-2(1H)-one

Step A

Preparation of 1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one

A mixture of 4-hydroxy-6-methyl-2-pyrone (2.5 g, 0.02 mol) and3-fluorobenzylamine (2.5 g, 0.02 mol) in n-butanol (15.0 mL) was heatedto reflux for 16 h under argon atmosphere. Butanol wad distilled invacuo, the residue was triturated with EtOAc, cooled and filtered theprecipitate. It was washed with cold EtOAc, and dried to give 0.86 g ofthe title compound as a pale yellow powder: ¹H—NMR δ: (CD₃OD) δ: 7.31(m, 1H), 7.0-6.85 (m, 2H), 6.83 (d, 1H, J=9.6,Hz), 5.96 (d, 1H, j=2.0Hz), 5.80 (d, 1H, J=2.0 Hz), 5.30 (s, 2H), and 2,24 (s, 3H); ES-MSm/z=234 (MH⁺).

Step B

Preparation of3-bromo-1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one

A mixture of 1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.8g, 0.0034 mol), NBS (0.64 g, 0.0036 mol) in dichloromethane (15.0 mL)was stirred at room temperature, under argon atmosphere. After 1.5 h,the reaction mixture was diluted with dichloromethane (15.0 mL), cooledand filtered the solids. The residue was washed with dichloromethane anddried in vacuo to give 0.93 g of the title compound as a white powder:¹H—NMR δ: (CD₃OD) δ: 7.33 (m, 1H), 7.2-6.8 (m, 3H), 6.07 (s, 1H), 5.34(s, 2H), 2.26 (s, 3H); ES-MS m/z=312 (MH⁺); HR-MS m/z calcd C₁₃H₁₂NO₂BrF312.0035, found 312.0016.

Step C

Preparation of3-bromo-1-(3-fluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate

To a suspension of3-bromo-1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.86 g,0.0028 mol) in dichloromethane (15.0 mL) cooled to −30° C.,triethylamine (0.5 mL, 0.004 mol) and triflic anhydride (0.7 mL, 0.0042mol) were added and stirred for 1 h. The resulting orange solution waspoured into ice cold water (25 mL) and extracted with dichloromethane(2×25 mL) The combined organic extracts were washed with water, dried(Na₂SO₄), filtered, and concentrated under reduced pressure. Theresulting residue was purified by silica gel flash chromatography using1:1 EtOAc/hexanes v/v to afford (85%) the title compound as a lightbrown solid: ¹H—NMR (CDCl₃) δ: 7.32 (m,1H), 7.0-6.85 (m, 3H), 6.18 (s,1H)₁ 5.32 (s, 2H), and 2.34 (s, 3H); ES-MS m/z=444 (MH⁺); HR-MS m/zcalcd C₁₄H₁₁NO₄BrF₄S 443.9528, found 443.9492.

Step D

Preparation of3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(phenylethynyl)pyridin-2(1H)-one

A solution of3-bromo-1-(3-fluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate (1.0 g, 0.0022 mol) and phenylacetylene (0.3mL, 0.0029 mol) in DMF (5.0 mL) was degassed using house vacuum, andpurged with argon (3 cycles) Diisopropylethylamine, (0.5 mL) was thenadded, followed by PdCl₂(PPh₃)₂ (0.36 g). The reaction mixture washeated at 65° C. for 1.5 h under argon atmosphere. The solvents weredistilled in vacuo, and the residue was purified by silica gel flashchromatography using EtOAc/hexanes (2:3 v/v) to afford 0.65 g (70%) ofthe title compound as a brown colored amorphous solid: ¹H—NMR (CD₃OD) δ:7.59 (m, 2H), 7.45-7.3 (m, 4H), 7.05-6.85 (m, 3H), 6.44 (s, 1H), 5.41(a, 2H), and 2.31 (s, 3H); ¹⁹F—NMR (CD₃OD) δ: −116.33 (m ); ES-MS,m/z=396 (MH⁺); HR-MS m/z cald C₂₁H₁₆NOBrF 396.0399, found 396.0373.

Step E

Preparation of3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(2-phenylethyl)pyridin-2(1H)-one

To a solution of3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(phenylethynyl)pyridin-2(1H)-one(0.55 g, 0.0014 mol) in EtOAc (10.0 mL) and EtOH (10.0 mL) was addedPtO2 (0.05 g) and stirred in an atmosphere of hydrogen gas at 15 psi for30 min. The catalyst was removed by filtration, the filtrate wasconcentrated and the residue was purified by silica gel flashchromatography using 25% EtOAc in hexanes as the eluent. The appropriatefractions were combined (visualized under UV) and concentrated todryness. The residue was crystallized from EtOAc/hexanes to provide 0.21g of the title compound as a light brown crystalline solid: ¹H—NMR δ:(CD₃OD) δ: 7.35 (m, 1H), 7.31-7.16 (m, 5H), 6.99(m, 1H), 6.91 (m, 1H),6.81 (m, 1H), 6.20 (s, 1H), 5.41 (s, 2H), 2.94 (m, 4H), and 2.24 (s,3H); ¹⁹F—NMR (CD₃OD) δ: −115.01 (m); ES-MS, m/z 400 (MH⁺) ; HR-MS m/zcalcd C₂₁H₂₀NOBrF 400.0712, found 400.0695.

Example 544-(benzyloxy)-3-bromo-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one

Step A

Preparation of3-acetyl-1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

A mixture of 2,6 dichlorophenylisocyanate (4.8 g, 0.025 mol), anddiketene (4.3 g, 0.05 mol) in toluene (15.0 mL) was heated to reflux for4 h under an atmosphere of argon. After removal of the solvent in vacuo,the residue was purified by silica gel flash chromatography usingEtOAc/hexanes (1:3 v/v). The appropriate fractions, as monitored by ESmass spectrometry (MH⁺ m/z=312) were combined and concentrated underreduced pressure. The resulting yellow solid (2.3 g) was furtherpurified by reverse-phase HPLC using 10-90% acetonitrile/water gradient(45 min) at a flow rate of 100 mL/min. The appropriate fractions, asmonitored by ES mass spectrometry (MH⁺ m/z=312) were combined andconcentrated to half the volume. The solid that separated was extractedwith EtOAc (2×25 mL). The combined extracts were washed with water,dried (Na₂SO₄), filtered, and concentrated to dryness to give the titlecompound (0.77 g) as a pale yellow powder: ¹H—NMR (CD₃OD) δ: 7.62 (m,2H), 7.52 (m, 1H), 6.19 (s, 1H), 2.59 (s, 3H), and 1.96 (s, 3H); ES-MSm/Z=312 (MH⁺); HR-MS, m/z calc C₁₄H₁₂NO₃Cl₂ 312.0189, found 312.0214.

Step B.

Preparation of1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

A mixture of3-acetyl-1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one 0.7g (0.002mol) in n-butanol(3.0 mL) containing sulfuric acid (1.5 mL) washeated at 120° C. for 4 h. The dark reaction mixture was cooled, addedice/water (25 mL), and extracted with EtOAc (2×25 ml). The combinedorganic extracts were washed with water, dried (Na₂SO₄), filtered,concentrated under reduced pressure and the resulting material waspurified by silica gel flash chromatography using 25% EtOAc in hexanesas the eluent to afford the title compound (0.14 g) as a pale yellowpowder: ¹H—NMR (CD3OD) δ: 7.6 (m, 2H), 7.48 (m, 1H), 6.10 (dd, 1H), 5.78(d, 1H, J=2.4 Hz), 1.91 (s, 3H); ES-MS m/z=2-70 (MH⁺); HR-MS, m/z calcC₁₂H₁₀NO₂Cl₂ 270.0083, found 270.0103.

Step C

Preparation of4-(benzyloxy)-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one

A mixture of 1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one(0.125 g, 0.46 mmol) and benzylbromide (0.1 mL) in DMF (2.5 mL) wasstirred at room temperature for 16 h. The reaction mixture was dilutedwith water (10.0 mL) and extracted with EtOAc (2×20 mL). The combinedorganic extracts were washed with water, dried (Na₂SO₄), filtered,concentrated under reduced pressure and the resulting material waspurified by silica gel flash chromatography using 25% EtOAc in hexanesto afford the title compound (0.11 g) as a pale yellow syrup: ¹H—NMR(CD₃OD) δ: 7.61 (m, 2H), 7.55-7.3 (m, 6H), 6.23 (d, 1H, J=2.0 Hz), 6.01(d, 1H, J=2.0 Hz), 5.12 (s, 2H), and 1.93 (s, 3H); ES-MS m/z=360 (MH⁺);HR-MS, m/z calc C₁₉H₁₆NO₂Cl₂, 360.0553, found. 360.0569.

Step D

Preparation of4-(benzyloxy)-3-bromo-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one

A mixture of4-(benzyloxy)-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one (0.1 g,0.278 mmol) and N-bromosuccinimide (0.055 g, 0.3 mmol) in dichloroethane(3.0 mL) was stirred at room temperature for 1 h, and heated at 60° C.under argon for 30 min. The reaction mixture was then diluted withdichloroethane (15 mL), washed with water, dried (Na₂SO₄), filtered,concentrated under reduced pressure and the resulting material wascrystallized from EtOAc/hexanes to furnish the title compound (0.075 g)as pale yellow needles. ¹H NMR (CD₃OD) δ: 7.64 (m, 2H), 7.55 (m, 3H),7.38 (m, 3H), 6.65 (s, 1H), 5.34 (s, 2H), and 2.00(s, 3H); ES-MS m/z=439(MH⁺); HR-MS, m/z calc C₁₉H₁₆NO₂Cl₂Br, 439.9635, found 439.9669.

Example-55 3-bromo-1-(3-fluorobenzyl)-4-(2-phenylethyl)pyridin-2(1H)-one

Step A

Preparation of 3-bromo-1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one

A mixture of 1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one 1.0 g, 0.004mo) and N-bromosuccinimide (0.85 g, 0.0048 mol) in dichloromethane (20.0mL) was stirred at room temperature for 30 min. The resulting whiteprecipitate was filtered, washed with dichloromethane, and dried invacuo to afford the title compound (1.1 g) as a white powder: ¹H NMR(CD₃OD) δ: 7.57 (d, 1H, J=7.6 Hz), 7.38 (m, 1H), 7.15 (m, 3H), 6.14 (d,1H, J=7.6 Hz), and 5.15 (s, 2H); ES-MS m/z=298 (MH⁺).

Step B

Preparation of 3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate

To a cold suspension (−30° C.) of3-bromo-1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one (1.0 g 0.0034 mol)in dichloromethane (10.0 mL), was added triethylamine (0.65 mL. 0.0046mol), followed by the addition of a solution of trifluoromethanesulfonicanhydride (0.73 mL, 0.0043 mol) in dichloromethane (3.0 mL). Theresulting mixture was stirred at −30° C. under an atmosphere of argonfor 1 h, and then poured into a mixture of ice/water (50 mL) anddichloromethane (25 mL). The organic phase was washed with water, dried(Na₂SO₄), filtered, concentrated under reduced. pressure and theresulting material was purified by flash chromatography using 25% EtOAcin hexanes to give the title compound (1.25 g, 84%) as a white solid:¹H—NMR (CDCl₃) δ: 7.35 (m, 2H), 7.03 (m, 3H), 6.29 (d, 1H, J=2.4 Hz),and 5.14 (S, 2H); ES-MS m/z=430 (MH⁺); HR-MS, m/z calc C₁₃H₉NO₄F₄Br,429.9366, found 429.9364.

Step C

Preparation of3-bromo-1-(3-fluorobenzyl)-4-(phenylethynyl)pyridin-2(1H)-one

To a degassed solution of3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate (0.6 g, 0.0014 mol) in DMF (5.00mL),diisopropylethylamine amine (0.4 ml, 0.0029 mol), phenylacetylene(0.3 mL. 0.0027 mol) and PdCl₂(PPh₃)₂ (0.2 g) were added and the mixturewas heated at 65° C. for 2 h under an atmosphere of argon. The solventswere then distilled in vacuo and the residue was purified by silica gelflash chromatography using 25% EtOAc in hexanes. Appropriate fractions,as monitored by ES-mass spectrometry (MH⁺ m/z=382) were combined andconcentrated under reduced pressure. The resulting residue wascrystallized from EtOAc/hexanes to afford the title compound (0.19 g) asshiny yellow flakes: ¹H NMR (CD₃OD) δ: 7.73 (d, 1H, J=7.2 Hz), 7,59 (m,2H), 7.44 (m, 4H) 7.1(m, 3H), 6,49 (d, 1H, J=7.2 Hz), 5.22 (s, 2H);ES-MS m/z=382 (MH⁺); HR-MS, m/z calc C₂₀H₁₄NOFBr, 382.0237, found382.0226.

Step D

Preparation of3-bromo-1-(3-fluorobenzyl)-4-(2-phenylethyl)pyridin-2(1H)-one

A suspension of3-bromo-1-(3-fluorobenzyl)-4-(phenylethynyl)pyridin-2(1H)-one (0.15 g,0.39 mmol) in EtoAc (5.0 mL), and EtOH (5.0 mL) containing PtO₂ (0.02 g)was stirred in an atmosphere of hydrogen (10 psi) in a Fischer-Porterbottle for 30 min. It was filtered, and the filtrate was concentratedunder reduced pressure. The resulting material was purified by silicagel chromatography using 25% EtOAc in hexane. The appropriate fractionswere combined, concentrated under reduced pressure, and the residue wascrystallized from EtOAc/hexanes to afford the title compound (0.08 g) asa white crystalline solid: ¹H—NMR (CD₃OD) δ: 7.58 (d, 1H, J=6.8 Hz),7.4-7.0 (m, 9H), 6.26 (d, 1H. J=6.8 Hz), 5.19 (s, 2H), 2.97 (m, 2H), and2.90 (m, 2H); ES-MS m/z=386 (MH⁺); HR-MS, m/z calc C₂₀H₁₈NOFBr,386.0550, found 386.0585.

Example 56 1-Benzyl-3-bromo-2-oxo-l,2-dihydropyridin-4-ylmethyl(phenyl)carbamate

Step A

Preparation of 1-Benzyl-2-oxo-1, 2-dihydropyridin-4-ylmethyl(phenyl)carbamate

To a chilled solution of 1-benzyl-4-hydroxypyridin-2(1H)-one (0.375 g,1.86 mmol) in anhydrous acetonitrile (10 mL) was added triethylamine(0.206 g, 2.04 mmol) followed by N-methyl-N-phenylcarbamoyl chloride(0.379 g, 2.24 mmol). The reaction mixture was stirred under nitrogenatmosphere at 0° C. for 30 min then at room temperature for 1 h. Thereaction was monitored by TLC (5% methanol in dichloromethane). Thesolvent was removed under reduced pressure and the residue was washedwith 10% citric acid and extracted with EtOAC. The organic extracts werecombined, washed with water dried over anhydrous Na₂SO₄, and filtered.The solvent was removed under reduced pressure to afford a yellow syrup.The residue was purified by flash chromatography (silica gel) using 5%MeOH in CH₂Cl₂ to give the desired product (0.382g, 61%) as a whitesemisolid.

MS and ¹H—NMR were consistent with the desired structure. ¹H—NMR(d₆-DMSO, 400 MHz) δ: 7.8 (d, 1H), 7.39 (m, 10H), 6.19 (s, 2H), 5.03 (s2H), 3.29 (s, 3H); HR-MS (ES) m/z calcd for C₂₀H₁₈N₂O₃ (MH⁺)=335.1396,observed 335.1418.

Step B

1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl methyl(phenyl)carbamate

To a solution of 1-benzyl-2-oxo-1,2-dihydropyridin-4-ylmethyl(phenyl)carbamate (0.38 g, 1.13 mmol) in anhydrous CH₂Cl₂ (7 mL)was added N-Bromosuccinimide (NBS, 0.24 g, 1.34 mmol). The reaction wasstirred overnight at room temperature under nitrogen atmosphere. Thereaction mixture was purified by flash chromatography (silica gel) usingEtOAc/hexanes (1:1 v/v). The appropriate fractions were collectedaccording to ES MS (M+H 413) and concentrated. The dried product showedabout 14% of di-brominated product by analytical HPLC. The compoundswere separated by reverse phase HPLC using a 10-90% acetonitrile inwater, 30 min gradient at a 100 mL/min flow rate, to afford (afterlyophilization) the salt of the desired compound. The salt was dilutedin EtOAc and washed with NaHCO₃ The organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated to afford the desiredcompound (0.271 g, 58%) as a beige solid.

MS and ¹H—NMR were consistent with the desired structure. ¹H—NMR(d₆-DMSO, 400 Hz) δ: 7.83 (d, 1H), 7.39 (m, 10H), 6.48 (s, 1H), 5.12(s,2H), 3.33 (s, 3H); HR-MS (ES) m/z calcd for C₂₀H₁₇ 0 ₃Br(MH⁺)=413.0495, observed 413.0496.

Example 57 4-(benzyloxy)-3-ethynyl-1-(3-fluorobenzyl)pyridin-2(1H)-one

Step A

Preparation of 4-,(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one

Heated a reaction mixture of4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.83 g, 15.6 mmol) inanhydrous acetonitrile (55 mL) and N-iodosuccinimide (NIS, 3.86 g, 17.1mmol) under nitrogen atmosphere at 65° C. for 4 h. The reaction mixturewas concentrated under reduced pressure and the residue was purified byflash chromatography (silica gel) using EtOAc/hexanes (1:1 v:v). Theappropriate fractions were collected according to ES MS (M+H 436) andwashed with Na₂SO₃ to remove the color impurities. The fractions wereconcentrated under reduced pressure and dried in vacuo to afford thedesired product (6.15 g, 90%) as a light yellow solid.

MS and ¹H—NMR were consistent with the desired structure. ¹H—NMR (CD₃OD,400 Hz) δ: 7.73 (d, 1H), 7.47 (d, 2H), 7.39 (m, 4H), 7.08 (m, 3H), 6.39(d, 1H), 5.29 (s, 2H), 5.19 (s, 2H); HR-MS (ES) m/z calcd forC₁₉H₁₅NO₂FI (MH⁺)=436.0210, observed 436.0196.

Step B

Preparation of4-(benzyloxy)-1-(3-fluorobenzyl)-3-[(trimethylsilyl)ethynyl]pyridin-2(1H)-one

Degassed a solution of4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one (2.01 g, 4.62mmol) in anhydrous acetonitrile (25 mL) under argon atmosphere.Triethylamine (1.11 g, 11 mmol) was added and quickly degassed. Thereaction mixture was chilled in an ice bath for 15 minutes before addingbistriphenylphosphine-palladium chloride (0.34 g, 0.48 mmol) and cuprousiodide (0.2 g). The reaction was stirred at room temperature for 30 minbefore heating at 60α C. under an atmosphere of argon for 2 h. Thereaction mixture was filtered through a bed of celite and the filtratewas concentrated under reduced pressure, The dark brown residue wasdiluted with CH₂Cl₂ (100 mL) and washed with water. The organic extractswere combined, dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure. The dark brown residue was purified by flashchromatography (silica gel): using 30% EtOAc in hexane. The appropriatefractions were combined and concentrated under reduced pressure toafford the desired product (1.34 g, 72%) as a light yellow solid.

MS and ¹H—NMR were consistent with the desired structure. ¹H—NMR (CD₃OD,400 Hz) δ: 7.74 (d, 1H), 7.47 (d, 2H), 7.35 (m, 4H), 7.09 (m, 3H), 6.46(d, 1H), 5.261 (s, 2H), 5.13 (s, 2H), 0.18 (s, 9H); HR-MS (ES) m/z calcdfor C₂₄H₂₄NO₂FSi (MH⁺)=406.1638, observed 406.1610.

Step C

Preparation of4-(benzyloxy)-3-ethynyl-1-(3-fluorobenzyl)pyridin-2(1H)-one

To a solution of4-(benzyloxy)-1-(3-fluorobenzyl)-3-[(trimethylsilyl)ethynyl]pyridin-2(1H)-one(1.31 g, 3.2 mmol) in anhydrous acetonitrile (25 mL) at 0° C. was addedtetrabutylammonium fluoride (0.611 g, 1.93 mmol). The reaction wasstirred at 0° C. for is min then for 1 h at room temperature. Thereaction was concentrated under reduced pressure and the residue wasdiluted with EtOAc and washed with water. The organic extracts werecombined, dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography(silica gel) using EtoAc in hexanes (1:1 v/v). The appropriate fractionswere combined and concentrated under reduced pressure to afford thedesired product (0.779 g, 72%) as a gold solid.

MS and ¹H—NMR were consistent with the desired structure. ¹H—NMR (CD₃OD,400 Hz) δ: 7.73 (d, 1H), 7.43 (d, 2H), 7.35 (m,4H), 7.09 (m,3H), 6.45(d, 1H), 5.271 (s, 2H), 5.13 (s,2H), 3.78 (s, 1H); HR-MS (ES) m/z calcdfor C₂₁H₁₆N0 ₂F (MH⁺)=334.1243, observed 334.1234.

Example 58 4-(benzylamino)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one

Step A

Preparation of 1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one

In a Fischer-Porter bottle, added a solution of4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.5 g, 14.56 mmol) inabsolute ethanol (20 ML). Flushed -the solution with nitrogen then addedpalladium catalyst (1.05 g). Sealed bottle and evacuated system. Thesystem was purged with hydrogen gas (2×15 psi) to check for leaks. Thereaction was charged with hydrogen (35 psi) and stirred at roomtemperature for 45 min. The system was evacuated and flushed withnitrogen. The reaction was filtered and the catalyst was carefullywashed with fresh ethanol. The filtrate was concentrated under reducedpressure and the residue was recrystallized in hot EtOAc to afford thedesired product (1.94 g, 61%) as a beige solid after drying in vacuo.

MS and ¹H—NMR were consistent with the desired structure. ¹H—NMR (CD₃OD,400 Hz) δ: 7.54 (d, 1H), 7.32 (m, 1H), 7.06 (m, 3H), 6.05 (dd, 1H), 5.83(s, 1H), 5.09 (s, 2H); HR-MS (ES) m/z calcd for C₁₂H₁₀NO₂F(MH⁺)=220.0774, observed 220.0787.

Step B

Preparation of 4-(benzylamino)-1-(3-fluorobenzyl)pyridin-2(1H)-one

Heated a reaction mixture of1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one (1.005 g, 4.5 mmol) inbenzylamine (15 mL) at reflux (185° C.) under nitrogen atmosphere for 24h. The reaction was monitored by ES-MS (MH+309). The solvent was removedby vacuum distillation to give a yellow residue. The residue wasrecrystallized in hot EtOAc, The white solid was allowed to cool andthen filtered to afford the desired product (0,862, 61%) after drying invacuo.

MS and ¹H—NMR were consistent with the desired structure. ¹H—NMR (CD₃OD,400 Hz) δ: 7.31 (m, 7H), 7.03 (m, 3H), 5.98 (dd, 1H), 5.45 (s, 1H) 5.00(s, 2H), 4.30 (s, 2H); HR-MS (ES) m/z calcd for C₁₉H₁₇N₂OF(MH⁺)=309.1403, observed 309.1375.

Step C

Preparation of4-(benzylamino)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one

To a solution of 4-(benzylamino) -1(3-fluorobenzyl)pyridin-2(1H)-one(0.50 g, 1.62 mmol) in anhydrous CH₂C₁ ₂ (10 mL) was addedN-bromosuccinimide (NBS, 0.30 g, 1.7 mmol). The reaction was stirred atroom temperature under a nitrogen atmosphere for 3 h. The reactionmixture was purified by flash chromatography (silica gel) using EtOAc inhexanes (1:1 v/v). The appropriate fractions were combined andconcentrated. The jelly like residue was recrystallized in hotEtoAc/hexanes (1:1 v/v) to afford the desired product (0.216 g, 35%) asa white solid after drying in vacuo.

MS and ¹H—NMR were consistent with the desired structure. ¹H—NMR (CD₃OD,400 Hz) δ: 7.41 (d, 1H), 7.31 (m, GH), 7.04 (m, 3H), 5.99 (d, 1H), 5.08(s, 2H) 4.53 (s, 2H); HR-MS (ES) m/z calcd for C₁₉H₁₆N₂OFBr(MH⁺)=387.0S08, observed 387.0504.

Biological Evaluation

p38 Kinase Assay

Cloning of human p38a:

The coding region of the human p38 cDNA was obtained byPCR-amplification from RNA isolated from the human monocyte cell lineTHP.1. First strand CDNA was synthesized from total RNA as follows: 2 μgof RNA was annealed to 100 ng of random hexamer primers in a 10 μlreaction by heating to 70° C. for 10 minutes followed by 2 minutes onice. cDNA was then synthesized by adding 1 μl of RNAsin (Promega,Madison, Wis.), 2 μl of 50 mM dNTP's, 4 μl of 5×buffer, 2 μl of 100 mMDTT and 1 μl (200 U) of Superscript II™ reverse transcriptase. Randomprimer, dNTP's and Superscript II™ reagents were all purchased fromLife-Technologies, Gaithersburg, Mass. The reaction was incubated at 42°C. for 1 hour. Amplification of p38 cDNA was performed by aliquoting 5μl of the reverse transcriptase reaction into a 100 μl PCR reactioncontaining the following: 80 μl dH.sub.2 0, 2. μl 50 mM dNTP's, 1 μleach of forward and reverse primers (50 pmol/μl), 10 μl of 10×buffer and1 μl Expand™ polymerase (Boehringer Mannheim). The PCR primersincorporated Bam HI sites onto the 5′ and 3′ end of the amplifiedfragment, and were purchased from Genosys. The sequences of the forwardand reverse primers were 5′-GATCGAGGATTCATGTCTCAGGAGAGGCCCA-31 and5′GATCGAGGATTCTCAGGACTCCATCTCTTC-3′ respectively. The PCR amplificationwas carried out in a DNA Thermal Cycler (Perkin Elmer) by repeating 30cycles of 94° C. for 1 minute, 60° C. for 1 minute and 68° C. for 2minutes. After amplification, excess primers and unincorporated dNTP'swere removed from the amplified fragment with a Wizard™ PCR prep(Promega) and digested with Bam HI (New England Biolabs). The Bam HIdigested fragment was ligated into BamHI digested pGEX 2T plasmid DNA(PharmaciaBiotech) using T-4 DNA: ligase (New England Biolabs) asdescribed by T. Maniatis, Molecular Cloning: A Laboratory Manual, 2nded. (1989). The ligation reaction was transformed into chemicallycompetent E. coli DH10B cells purchased from Life-Technologies followingthe manufacturer's instructions. Plasmid DNA was isolated from theresulting bacterial colonies using a Promega Wizard™ miniprep kit.Plasmids containing the appropriate Bam HI fragment were sequenced in aDNA Thermal Cycler (Perkin Elmer) with Prism™ (Applied Biosystems Inc.).cDNA clones were identified that coded for both human p38a isoforms (Leeet al. Nature 3721, 739). One of the clones that contained the cDNA forp38a-2 ,(CSB-2) inserted in the cloning site of PGEX 2T, 3′ of the GSTcoding region was designated pMON 35802. The sequence obtained for thisclone is an exact match of the ‘cDNA clone reported by Lee et al. Thisexpression plasmid allows for the production of a GST-p38a fusionprotein.

Expression of human p38a

GST/p38a fusion protein w as expressed from the plasmid pMON 35802 in E.coli, stain DH10B (Life Technologies, Gibco-BRL). Overnight cultureswere grown in Luria Broth (LB) containing 100 mg/ml ampicillin. The nextday, 500 ml of fresh LB was inoculated with 10 ml of overnight culture,and grown in a 2 liter flask at 37° C. with constant shaking until theculture reached an absorbance of 0.8 at 600 nm. Expression of the fusionprotein was induced by addition of isopropyl b-D-thiogalactosidase(IPTG) to a final concentration of 0.05 mM, The cultures were shaken forthree hours at room temperature, and the cells were harvested bycentrifugation. The cell pellets were stored frozen until proteinpurification.

Purification of P38 Kinase-Alpha

All chemicals were from Sigma Chemical Co. unless noted. Twenty grams ofE. coli cell pellet collected from five 1 L shake flask fermentationswas resuspended in a volume of PBS (140 mM NaCl, 2.7 mM KCl, 10 mMNa.sub.2 HPO.sub.4, 1.8 mM KH.sub.2 PO.sub.4, pH 7.3) up to 200 ml. Thecell suspension was adjusted to 5 mM DTT with 2 M DTT and then splitequally into five 50 ml Falcon conical tubes. The cells were sonnicated(Ultrasonics model W375) with a 1 cm probe for 3.times.1 minutes(pulsed) on ice. Lysed cell material was removed by centrifugation(12,000×g, 15 minutes) and the clarified supernatant applied toglutathione-sepharose resin (Pharmacia).

Glutathione-Sepharose Affinity Chromatography

Twelve ml of a 50% glutathione sepharose-PBS suspension was added to 200ml clarified supernatant and incubated batchwise for 30 minutes at roomtemperature. The resin was collected by centrifugation (600.times.g, 5min) and washed with 2.times.150 ml PBS/1% Triton X-100, followed by4.times.40 ml PBS. To cleave the p38 kinase from the GST-p38 fusionprotein, the glutathione-sepharose resin was resuspended in 6 ml PBScontaining 250 units thrombin protease (Pharmacia, specificactivity >7500 units/mg) and mixed gently for 4 hours at roomtemperature. The glutathione-sepharose resin was removed bycentrifugation (600.times.g; 5 min) and washed 2.times.6 ml with PBS.The PBS wash fractions and digest supernatant containing p38 kinaseprotein were pooled and adjusted to 0.3 mM PMSF.

Mono Q Anion Exchange Chromatography

The thrombin-cleaved p38 kinase was further purified by FPLC-anionexchange chromatography. Thrombin-cleaved sample was diluted 2-fold withBuffer A (25 mM HEPES, pH 7.5, 25 mM beta-glycerophosphate, 2 mM DTT, 5%glycerol) and injected onto a Mono Q HR 10/10 (Pharmacia) anion exchangecolumn equilibrated with Buffer A. The column was eluted with a 160 ml0.1 M-0.6 M NaCl/Buffer A gradient (2 ml/minute flowrate). The p38kinase peak eluting at 200 mM NaCl was collected and concentrated to 3-4ml with a Filtron 10 concentrator (Filtron Corp.).

Sephacryl S100 Gel Filtration Chromatography

The concentrated Mono Q-p38 kinase purified sample was purified by gelfiltration chromatography (Pharmacia HiPrep 26/60 Sephacryl S100 columnequilibrated with Buffer B (50 mM HEPES, pH 7.5, 50 mM NaCl, 2 mM DTT,5% glycerol)). Protein was eluted from the column with Buffer B at a 0.5ml/minute flowrate and protein was detected by absorbance at 280 nm.Fractions containing p38 kinase (detected by SDS-polyacrylamide gelelectrophoresis) were pooled and frozen at -80° C. Typical purifiedprotein yields from 5 L E. coli shake flasks fermentations were 35 mgp38 kinase.

In Vitro Assay

The ability of compounds to inhibit human p38 kinase alpha was evaluatedusing two in vitro assay methods. In the first method, activated humanp38 kinase alpha phosphorylates a biotinylated substrate, PHAS-I(phosphorylated heat and acid stable protein-insulin inducible), in thepresence of gamma ³²p-ATP (³²P-ATP). PHAS-I was biotinylated prior tothe assay and provides a means of capturing the substrate, which isphosphorylated during the assay. p38 Kinase was activated by MKK6.Compounds were tested in 10 fold serial dilutions over the range of 100μM to 0,001 μM using 1% DMSO. Each concentration of inhibitor was testedin triplicate.

All reactions were carried out in 96 well polypropylene plates. Eachreaction well contained 25 mM HEPES pH 7.5, 10 mM magnesium acetate and50 μM unlabeled ATP. Activation of p38 was required to achievesufficient signal in the assay. Biotinylated PHAS-I was used at 1-2 μgper 50 μl reaction volume, with a final concentration of 1.5 μM.Activated human p38 kinase alpha was used at 1 μg per 50 μl reactionvolume representing a final concentration of 0.3 μM. Gamma ³²P-ATP wasused to follow the phosphorylation of PHAS-I. ³²P-ATP has a specificactivity of 3000 Ci/mmol and was used at 1.2 μCi per 50 μl reactionvolume. The reaction proceeded either for one hour or overnight at 30°C.

Following incubation, 20 μl of reaction mixture was transferred to ahigh capacity streptavidin coated filter plate (SAM-streptavidin-matrix,Promega) prewetted with phosphate buffered saline, The transferredreaction mix was allowed to contact the streptavidin membrane of thePromega plate for 1-2 minutes. Following capture of biotinylated PHAS-Iwith ³²p incorporated, each well was washed to remove unincorporated³²p-ATP three times with 2M NaCl, three washes of 2M NaCl with 1%phosphoric, three washes of distilled water and finally a single wash of95% ethanol. Filter plates were air-dried and 20 μl of scintillant wasadded. The plates were sealed and counted.

A second assay format was also employed that is based on p38 kinasealpha induced phosphorylation of EGFRP (epidermal growth factor receptorpeptide, a 21 mer) in the presence ³³P-ATP. Compounds were tested in 10fold serial dilutions over the range of 100 μM to 0.001 μM in 1% DMSO.Each concentration of inhibitor was tested in triplicate. Compounds wereevaluated in 50 μl reaction volumes in the presence of 25 mM Hepes pH7.5, 10 mM magnesium acetate, 4% glycerol, 0.4% bovine serum albumin,0.4 mM DTT, 50 μM unlabeled ATP, 25 μg EGFRP (200 μM), and 0.05 μCi³³p-ATP. Reactions were initiated by addition of 0.09 μg of activated,purified human GST-p38 kinase alpha. Activation was carried out usingGST-MKK6 (5:1,p38:MKK6) for one hour at 30° C. in the presence of 50 μMATP. Following incubation for 60 minutes at room temperature, thereaction was stopped by addition of 150 μl of AG 1.times.8 resin in 900mM sodium formate buffer, pH 3.0 (1 volume resin to 2 volumes buffer).The mixture was mixed three times with pipetting and the resin wasallowed to settle. A total of 50 μl of clarified solution head volumewas transferred from the reaction wells to Microlite-2 plates. 150 μl ofMicroscint 40 was then added to each well of the Microlite plate, andthe plate was sealed, mixed, and counted.

TNF Cell Assays

Method of Isolation of Human Peripheral Blood Mononuclear Cells:

Human whole blood was collected in Vacutainer tubes containing EDTA asan anticoagulant. A blood sample (7 ml) was carefully layered over 5 mlPMN Cell Isolation Medium (Robbins Scientific) in a 15 ml round bottomcentrifuge tube. The sample was centrifuged at 450-500.times.g for 30-35minutes in a swing out rotor at room temperature, After centrifugation,the top band of cells were removed and washed 3 times with PBS w/ocalcium or magnesium. The cells were centrifuged at 400.times.g for 10minutes at room temperature. The cells were resuspended in MacrophageSerum Free Medium.(Gibco BRL) at a concentration of 2 million cells/mi.

LPS Stimulation of Human PBMs

PBM cells (0.1 ml, 2 million/ml) were co-incubated with 0.1 ml compound(10-0.41 μM, final concentration) for 1 hour in flat bottom 96 wellmicrotiter plates. Compounds were dissolved in DMSO initially anddiluted in TCM for a final concentration of 0.1% DMSO. LPS (Calbiochem,20 ng/ml, final concentration) was then added at a volume of 0.010 ml.Cultures were incubated overnight at 37° C. Supernatants were thenremoved and tested by ELISA for TNF-a and ILl-b. Viability was analyzedusing MTS. After 0.1 ml supernatant was collected, 0.020 ml MTS wasadded to remaining 0.1 ml cells. The cells were incubated at 37° C. for2-4 hours, then the O.D. was measured at 490-650 nM.

Maintenance and Differentiation of the U937 Human Histiocytic LymphomaCell Line

U937 cells (ATCC) were propagated in RPMI 1640 containing 10% fetalbovine serum, 100 IU/ml penicillin, 100 μg/ml streptomycin, and 2 mMglutamine (Gibco). Fifty million cells in 100 ml media were induced toterminal monocytic differentiation by 24 hour incubation with 20 ng/mlphorbol 12-myristate 13-acetate (Sigma). The cells were washed bycentrifugation (200.times.g for 5 min) and resuspended in 100 ml freshmedium. After 24-48 hours, the cells were harvested, centrifuged, andresuspended in culture medium at 2 million cells/ml.

LPS Stimulation of TNF Production by U937 Cells

U937 cells (0.1 ml, 2 million/ml) were incubated with 0.1 ml compound(0.004-50 μM, final concentration) for 1 hour in 96 well microtiterplates. Compounds were prepared as 10 mM stock solutions in DMSO anddiluted in culture medium to yield a final DMSO concentration of 0.1% inthe cell assay. LPS (E coli, 100 ng/ml final concentration) was thenadded at a volume of 0.02 ml. After 4 hour incubation at 370° C., theamount of TNF-.alpha. released in the culture medium was quantitated byELISA. Inhibitory potency is expressed as IC50 (μM).

Rat Assay

The efficacy of the novel compounds in blocking the production of TNFalso was evaluated using a model based on rats challenged with LPS. MaleHarlen Lewis rats [Sprague Dawley Co.] were used in this model. Each ratweighed approximately 300 g and was fasted overnight prior to testing.Compound administration was typically by oral gavage (althoughintraperitoneal, subcutaneous and intravenous administration were alsoused in a few instances) 1 to 24 hours prior to the LPS challenge. Ratswere administered 30 μg/kg LPS [salmonella typhosa, Sigma Co.]intravenously via the tail vein. Blood was collected via heart puncture1 hour after the LPS challenge. Serum samples were stored at −20° C.,until quantitative analysis of TNF-.alpha. by EnzymeLinked-Immuno-Sorbent Assay (“ELISA”) [Biosource].

Additional details of the assay are set forth in Perretti, M., et al.,Br. J. Pharmacol. (1993), 110, 868-874, which is incorporated byreference in this application.

Mouse Assay

Mouse Model of LPS-Induced TNF Alpha Production

TNF alpha was induced in 10-12 week old BALB/c female mice by tail veininjection with 100 ng lipopolysaccharide (from S. Typhosa) in 0.2 mlsaline. One hour later mice were bled from the retroorbital sinus andTNF concentrations in serum from clotted blood were quantified by ELISA.Typically, peak levels of serum TNF ranged from 2-6 ng/ml one hour afterLPS injection.

The compounds tested were administered to fasted mice by oral gavage asa suspension in 0.2 ml of 0.5% methylcellulose and 0.025% Tween 20 inwater at 1 hour or 6 hours prior to LPS injection. The 1 hour protocolallowed evaluation of compound potency at Cmax plasma levels whereas the6 hour protocol allowed estimation of compound duration of action.Efficacy was determined at each time point as percent inhibition ofserum TNF levels relative to LPS injected mice that received vehicleonly.

Induction and Assessment of Collagen-Induced Arthritis in Mice

Arthritis was induced in mice according to the procedure set forth in J.M. Stuart, Collagen Autoimmune Arthritis, Annual Rev. Immunol. 2:199(1984), which is incorporated herein by reference. Specifically,arthritis was induced in 8-12 week old DBA/1 male mice by injection of50 μg of chick type II collagen (CII) (provided by Dr. Marie Griffiths,Univ. of Utah, Salt Lake City, Utah) in complete Freund's adjuvant(Sigma) on day 0 at the base of the tail. Injection volume was 100 μl.Animals were boosted on day 21 with 50 pg of CII in incomplete Freund'sadjuvant (100 μl volume). Animals were evaluated several times each weekfor signs of arthritis. Any animal with paw redness or swelling wascounted as arthritic. Scoring of arthritic paws was conducted inaccordance with the procedure set forth in Wooley et al., GeneticControl of Type II Collagen Induced Arthritis in Mice: FactorsInfluencing Disease Suspectibility and Evidence for Multiple MHCAssociated Gene Control., Trans. Proc., 15:180 (1983). Scoring ofseverity. was carried out using a score of 1-3 for each paw (maximalscore of 12/mouse). Animals displaying any redness or swelling of digitsor the paw were scored as 1. Gross swelling of the whole paw ordeformity was scored as 2. Ankylosis of joints was scored as 3. Animalswere evaluated for 8 weeks. 8-10 animals per group were used.

Results obtained using the above-described assays are set forth inTables I, II, and III below. p38 Assay results are expressed as IC₅₀(μm). TABLE I Example Structure p38 Alpha IC50 (uM) A

0.841 (n = 15) B

0.403 (n = 7) C

0.0646 (n = 2) D

0.17 E

0.129 (n = 2) F

0.132 (n = 2) G

0.179 (n = 2) H

0.260 (n = 2) I

0.210 (n = 2) J

0.700 (n = 3) K

0.219 L

0.294 (n = 2) M

0.360 (n = 2) N

0.381 (n = 2) O

0.394 (n = 3) P

0.403 (n = 2) Q

0.365 R

0.398 S

0.498 (n = 2) T

0.423 U

0.427 V

0.455 (n = 2) W

0.45 X

0.45 Y

0.489 Z

0.507 AA

0.691 (n = 2) BB

0.632 (n = 2) CC

0.536 DD

0.554 (n = 2) EE

0.572 (n = 2) FF

0.581 GG

0.785 (n = 2) HH

0.746 II

0.873 (n = 2) JJ

0.850 (n = 2) KK

0.997 (n = 2)

In the preceding table, the “n” value in the parenthesis is the numberof times that the particular compound was assayed. If an “n” value isnot reported, then n=1. If n is not 1, then the average from all trialsis reported. TABLE II Example Structure p38A LL

1.73 MM

1.38 NN

2.03 OO

2.46 PP

1.90 QQ

2.41 RR

6.80 SS

1.25 0.921 TT

1.45 UU

1.14 VV

14.3  WW

>100      XX

 0.219 YY

ZZ

3.67 AAA

1.99 BBB

>100      CCC

1.60 DDD

6.63 EEE

11.5  FFF

41.6  GGG

13.2  HHH

18.0  III

90.9  JJJ

7.99 3.46 KKK

25.6 73.0 47.2 22.3  LLL

MMM

1.53 NNN

24.9  OOO

>100      PPP

35.8  QQQ

3.31 RRR

56.5  SSS

9.86 TTT

UUU

VVV

>100      WWW

81.8  XXX

51.5  YYY

2.23 ZZZ

AAAA

>100      BBBB

3.60 CCCC

77.6  DDDD

2.51 EEEE

26.4 59.2 49.0  FFFF

33.8  GGGG

31.9  HHHH

IIII

>100      JJJJ

KKKK

>100      LLLL

MMMM

NNNN

64.8  OOOO

38.7 

TABLE III p38 Alpha Example Structure IC₅₀ (uM) PPPP

0.0970 (n = 2) QQQQ

0.199 (n = 2) RRRR

0.132 (n = 2) SSSS

0.141 (n = 2) TTTT

0.175 UUUU

0.192 (n = 2) VVVV

0.183 WWWW

0.260 (n = 2) XXXX

0.282 (n = 2) YYYY

0.339 (n = 2) ZZZZ

0.381 (n = 2) AAAAA

0.394 (n = 3) BBBBB

0.455 (n = 2) CCCCC

0.663 (n = 2) DDDDD

0.691 (n = 2) EEEEE

0.684 (n = 2) FFFFF

1.08 (n = 2) GGGGG

1.04 (n = 2) HHHHH

1.18 (n = 2) IIIII

1.14 JJJJJ

1.55 (n = 2) KKKKK

1.45 LLLLL

1.71 (n = 2) MMMMM

1.53 NNNNN

1.69 (n = 2) OOOOO

1.6 PPPPP

1.76 (n = 2) QQQQQ

1.73 RRRRR

1.85 (n = 2) SSSSS

1.99

In the preceding tables, the “n” value relates to the number of timesthat the assay of the particular compound was performed. If an “n” valueis not reported, then the “n” value is 1.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, hard or soft capsule, lozenges,dispensable powders, suspension, or liquid. The pharmaceuticalcomposition is preferably made in the form of a dosage unit containing aparticular amount of the active ingredient. Examples of such dosageunits are tablets or capsules.

The active ingredient may also be administered by injection (IV, IM,subcutaneous or jet) as a composition wherein, for example, saline,dextrose, or water may be used as a suitable carrier. The pH of thecomposition may be adjusted, if necessary, with suitable acid, base, orbuffer. Suitable bulking, dispersing, wetting or suspending agents,including mannitol and PEG 400, may also be included in the composition.A suitable parenteral composition can also include a compound formulatedas a sterile solid substance, including lyophilized powder, in injectionvials. Aqueous solution can be added to dissolve the compound prior toinjection.

The amount of therapeutically active compounds that are administered andthe dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention depends on a variety of factors,including the age, weight, sex and medical condition of the subject, theseverity of the inflammation or inflammation related disorder, the routeand frequency of administration, and the particular compound employed,and thus may vary widely. The pharmaceutical compositions may containactive ingredients in the range of about 0.1 to 1000 mg, preferably inthe range of about 7.0 to 350 mg. A daily dose of about 0.01 to 100mg/kg body weight, preferably between about 0.1 and about 50 mg/kg bodyweight and most preferably between about 0.5 to 30 mg/kg body weight,may be appropriate. The daily dose can be administered in one to fourdoses per day. In the case of skin conditions, it may be preferable toapply a topical preparation of compounds of this invention to theaffected area two to four times a day.

For disorders of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical gel, spray,ointment or cream, or as a suppository, containing the activeingredients in a total amount of, for example, 0.075 to 30% w/w,preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-l,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound, which enhances absorption or penetrationof the active ingredient through the skin or other affected areas.Examples of such dermal penetration enhancers include dimethylsulfoxideand related analogs. The compounds of this invention can also beadministered by a transdermal device. Preferably topical administrationwill be accomplished using a patch either of the reservoir and porousmembrane type or of a solid matrix variety. In either case, the activeagent is delivered continuously from the reservoir or microcapsulesthrough a membrane into the active agent permeable adhesive, which is incontact with the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane. The transdermal patch may include the compound in a suitablesolvent system with an adhesive system, such as an acrylic emulsion, anda polyester patch. The oily phase of the emulsions of this invention maybe constituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifiers with orwithout stabilizers make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase, which forms the oily, dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others. The choice of suitable oils or fats for the formulation isbased on achieving the desired cosmetic properties, since the solubilityof the active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono-or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The antiinflammatory active ingredients are preferablypresent in such formulations in a concentration of 0.5 to 20%,advantageously 0.5 to 10% and particularly about 1.5% w/w. Fortherapeutic purposes, the active compounds of this combination inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein R₁ is H, halogen,alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy, arylalkyl, CN,alkanoyl, alkoxy, alkoxyalkyl, or arylalkanoyl, wherein the aryl portionof arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted orsubstituted with 1, 2, 3, 4, or 5 groups that are independently halogen,C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂H;wherein the alkyl portion of the alkyl, hydroxyalkyl, arylalkoxy,arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups isunsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, methoxy, ethoxy or spirocyclopropyl; R₂ isarylalkoxy, aryloxy, OH, halogen, arylthioalkoxy, alkoxy,—OC(O)NH(CH₂)_(n)aryl, —OC(O)N(alkyl) (CH₂)_(n)aryl, alkyl,alkoxyalkoxy, dialkylamino, heteroaryl, heterocycloalkyl, or CO₂H,wherein n is 0 1, 2, 3, 4, 5 or 6; the aryl portion of arylalkoxy,aryloxy, arylthioalkoxy, —OC(O)NH(CH₂)_(n)aryl, and —OC(O)N(alkyl)(CH₂)_(n)aryl or the heteroaryl and heterocycloalkyl groups isunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently halogen, haloalkyl, heteroaryl, heteroarylalkyl, NR₆R₇,NR₆R₇alkyl, —OC(O)NR₆R_(7,) wherein R₆ and R₇ are independently at eachoccurrence H, alkyl, alkoxy, alkanoyl, arylalkyl, arylalkoxy, orarylalkanoyl, wherein the aryl portion of arylalkyl, arylalkoxy, orarylalkanoyl is unsubstituted or substituted with 1, 2, or 3 groups thatare independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy; R₃is halogen, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl,arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy, —OC(O)N alkyl)(CH₂)_(n)aryl, aryloxy, arylthio, thioalkoxy, arylthioalkoxy, alkenyl,NR₆R₇ or alkyl, wherein the aryl portion of arylalkoxycarbonyl,aryloxycarbonyl, arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy,—OC(O)N(alkyl) (CH₂)_(n)aryl, and arylthioalkoxy, is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently, halogen,alkoxy, alkyl, haloalkyl, or haloalkoxy, wherein n is 0, 1, 2, 3, 4, 5,or 6; or R₂, R₃ and the carbons to which they are attached form an aryl,heterocycloalkyl or a heteroaryl ring, which is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently alkyl, alkoxy,halogen, arylalkyl, arylalkoxy, heteroarylalkyl, heterocycloalkylalkyl,CN, NO₂, haloalkyl, or haloalkoxy; R₄ is H, alkyl, arylalkoxy,arylalkyl, hydroxyalkyl, haloalkyl, NR₆R₇alkyl, alkoxy, alkoxyalkyl, oralkoxyalkoxy, wherein the aryl portion of arylalkoxy, arylalkyl isunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, orhaloalkoxy; and R₅ is arylalkyl, alkyl, aryl, alkoxy,heterocycloalkylalkyl, heteroarylalkyl, heterocycloalkyl, or heteroaryl,wherein each of the above is unsubstituted or substituted with 1, 2, 3,4, or 5 groups that are independently alkyl, halogen, alkoxy,arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, CO₂H, CN,amidinooxime, NR₆R₇, NR₆R₇alkyl, —C(O)NR₆R_(7,) amidino, haloalkyl, orhaloalkoxy.
 2. A compound or salt of the formula:

or a pharmaceutically acceptable salt thereof, wherein R₁ is alkanoyl,halogen, arylalkanoyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, orcarboxaldehyde, wherein the aryl portion of arylalkyl, and arylalkanoylis unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN, haloalkyl,haloalkoxy or CO₂H; the alkyl portion of the hydroxyalkyl, arylalkyl,alkanoyl, alkoxyalkyl and arylalkanoyl groups are unsubstituted orsubstituted with 1, 2, or 3 groups that are independently halogen,methoxy, ethoxy or spirocyclopropyl; R₂ is arylalkoxy, aryloxy, OH,halogen, arylthioalkoxy, alkoxy, —OC(O)NH(CH₂)_(n)aryl, —OC(O)N(alkyl)(CH₂)_(n)aryl, alkyl, alkoxyalkoxy, dialkylamino, pyridyl, pyrimidyl,pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl,triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl,thiazolyl, thiophenyl, or CO₂H, wherein n is 0, 1, 2, 3, 4, 5 or 6; thearyl portion of. arylalkoxy, aryloxy, arylthioalkoxy,—OC(O)NH(CH₂)_(n)aryl, and —OC(O)N(alkyl) (CH₂)_(n)aryl or theheteroaryl and heterocycloalkyl groups is unsubstituted or substitutedwith 1, 2, 3, 4, or 5 groups that are independently halogen, haloalkyl,heteroaryl, heteroarylalkyl, NR₆R₇, NR₆R₇alkyl, —OC(O)NR₆R₇, wherein R₆and R₇ are independently at each occurrence H, alkyl, alkoxy, alkanoyl,arylalkyl, arylalkoxy, or arylalkanoyl, wherein the aryl portion. ofarylalkyl, arylalkoxy, or arylalkanoyl is unsubstituted or substitutedwith 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl,haloalkyl, or haloalkoxy; R₃ is halogen, arylalkoxycarbonyl,aryloxycarbonyl, arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy,—OC(O)N(alkyl) (CH₂)_(n)aryl, aryloxy, arylthio, thioalkoxy,arylthioalkoxy, or alkenyl, NR₆R₇ or—alkyl, wherein the aryl portion ofarylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, —OC(O)NH(CH₂)_(n)aryl,arylalkoxy, —OC(O)N(alkyl) (CH₂)_(n)aryl, and arylthioalkoxy, isunsubstituted or substituted with 1, 2, or 3 groups that areindependently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy, whereinn is 0, 1, 2, 3, 4, 5, or 6; or R₂, R₃ and the carbons to which they areattached form an aryl, heterocycloalkyl or a heteroaryl ring, which isunsubstituted or substituted with 1, 2, or 3 groups that areindependently alkyl, alkoxy, halogen, arylalkyl, arylalkoxy,heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂₁ haloalkyl, orhaloalkoxy; R₄ is H, alkyl, arylalkoxy, arylalkyl, hydroxyalkyl,haloalkyl, NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein Thearyl portion of arylalkoxy, arylalkyl is unsubstituted or substitutedwith 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy,alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and R₅ is arylalkyl,alkyl, aryl, alkoxy, heterocycloalkylalkyl, heteroarylalkyl,arylthioalkyl, heterocycloalkyl, or heteroaryl, wherein each of theabove is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups thatare independently alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy,alkoxycarbonyl, arylalkoxycarbonyl, CO₂H, CN, amidinooxime, NR₆R₇,NR₆R₇alkyl, —C(O)NR₆R₇, amidino, haloalkyl, or haloalkoxy.
 3. A compoundor salt according to claim 2 wherein R₂ is arylalkoxy, aryloxy, OH,halogen, arylthioalkoxy, alkoxy, alkyl, alkoxyalkoxy,—OC(O)NH(CH₂)_(n)phenyl —OC(O)N(alkyl)(CH₂)_(n)phenyl, pyridyl,pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl,benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl,hexahydropyrimidinyl, or thiazolyl, thiophenyl, wherein n is 0, 1, 2, 3,4, 5 or 6; and the above are unsubstituted or substituted with 1, 2, 3,4, or 5 groups that are independently halogen, haloalkyl, or thiophenyl.4. A compound or salt according to claim 2 wherein R₅ isphenyl(C₁-C₆)alkyl, (C₁-C₆)alkyl, phenyl, naphthyl, (C₁-C₆)alkoxy,piperidinyl(C₁-C₆)alkyl, pyrrolyl(C₁-C₆)alkyl, pyrrolidinyl(C₁-C₆)alkyl,imidazolidinyl(C₁-C₆)alkyl, pyrazolyl(C₁-C₆)alkyl,imidazolyl(C₁-C₆)alkyl, tetrahydropyridinyl(C₁-C₆)alkyl,thiophenyl(C₁-C₆)alkyl, arylthio(C₁-C₆)alkyl, pyridyl, orpyridyl(C₁-C₆)alkyl, wherein each of the above is unsubstituted orsubstituted with 1, 2, 3, 4, or 5 groups that are independently(C₁-C₄)alkyl, fluoro, chloro, bromo, (C₁-C₄)alkoxy, phenyl(C₁-C₄)alkoxy,thio (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, phenyl(C₁-C₄)alkoxycarbonyl,CO₂H, CN, amidinooxime, NR₆R₇, NR₆R₇alkyl, —C(O)NR₆R₇, amidino, CF₃,—CF₂CF₃, OCF₃ or OCF₂CF₃.
 5. A compound or salt according to claim 2wherein R₁ is halogen, (C₁-C₆)alkanoyl, phenyl(C₁-C₆)alkanoyl,naphthyl(C₁-C₆)alkanoyl, naphthyl(C₁-C,)alkyl, phenyl(C₁-C₆)alkyl,alkoxyalkyl, hydroxyalkyl, or carboxaldehyde, wherein the phenyl andnaphthyl portions of the above are unsubstituted or substituted with 1,2, 3, 4, or 5 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H; the alkyl portion of thehydroxyalkyl, arylalkyl, alkanoyl, alkoxyalkyl and arylalkanoyl groupsare unsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, methoxy, or ethoxy.
 6. A compound or saltaccording to claim 2 wherein R₃ is halogen, phenylalkoxycarbonyl,phenyloxycarbonyl, phenyl(C₁-C₆)alkyl, —OC(O)NH(CH₂)_(n)aryl,phenylalkoxy, —OC(O)N(alkyl) (CH₂)_(n)aryl, phenyloxy, naphthyloxy,phenylthio, thioalkoxy, arylthioalkoxy, (C₂-C₆)alkenyl, NR₆R₇ or alkyl,wherein the phenyl, naphthyl, and aryl portions of arylalkoxycarbonyl₁,aryloxycarbonyl, arylalkyl, —OC (O)NH (CH₂)_(n)aryl, arylthioalkoxy,arylalkoxy, and—OC(O)N(alkyl) (CH₂)_(n)aryl, are unsubstituted orsubstituted with 1, 2, or 3 groups that are independently, halogen,alkoxy, alkyl, CF₃, or OCF₃; and wherein n is 0, 1, 2, 3, 4, 5, or
 6. 7.A compound or salt according to claim 2 wherein R₄ is H, (C₁-C₆)alkyl,phenylalkoxy, phenyl(C₁-C₆)alkyl, hydroxyalkyl, haloalkyl, NR₆R₇alkyl,(C₁-C₆)alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl portionof the above groups is unsubstituted or substituted with 1, 2, 3, 4, or5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro,CF_(3,) or OCF₃.
 8. A compound or salt according to claim 2 wherein R₁is halogen, (C₁-C₆)alkanoyl, phenyl(C₁-C₆)alkanoyl,naphthyl(C₁-C₆)alkanoyl, naphthyl(C₁-C,)alkyl, phenyl(C₁-C₆)alkyl,alkoxyalkyl, hydroxyalkyl, or carboxaldehyde, wherein the phenyl andnapthyl portions of the above are unsubstituted or substituted with 1,2, 3, 4, or 5 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H; the alkyl portion of the abovegroups are unsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, methoxy, or ethoxy. R₂ is phenylalkoxy, aryloxy,OH, halogen, phenylthioalkoxy, alkoxy, alkyl, alkoxyalkoxy, —OC (O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl) (CH₂)_(n)phenyl, pyridyl, pyrimidyl,pyridazyl, pyrazolyl, or thiophenyl, wherein n is 0, 1, 2, 3, or 4, andthe above groups are unsubstituted or substituted with 1, 2, 3, 4, or 5groups that are independently halogen, halo(C₁-C₄)alkyl, thiophenyl; R₃is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl, phenyl(C₁-C₆)alkyl,phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, arylthioalkoxy,(C₂-C₆)alkenyl, NR₆R₇ or alkyl, wherein the phenyl, naphthyl, and arylportions of arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl,—OC(O)NH(CH₂)_(n)aryl arylthioalkoxy, arylalkoxy, and—OC(O)N(alkyl)(CH₂)_(n)aryl, are unsubstituted or substituted with 1, 2, or 3 groupsthat are independently, halogen, alkoxy, alkyl, CF₃, or OCF₃, wherein nis 0, 1, 2, 3, 4, 5, or 6; or R₄ is H, (C₁-C₆)alkyl, phenylalkoxy,phenyl(C₁-C₆)alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, oralkoxyalkoxy, wherein the phenyl portion of the above groups areunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently halogen, hydroxy, alkoxy, alkyl, nitro, CF₃, or OCF₃. R₅is phenyl(C₁-C₆)alkyl, (C₁-C₆)alkyl, phenyl, naphthyl, pyridyl,(C₁-C₆)alkoxy, piperidinyl(C₁-C₆)alkyl, pyrrolyl(C₁-C₆)alkyl,imidazolidinyl(C₁-C₆)alkyl, pyrazolyl(C₁-C₆)alkyl,imidazolyl(C₁-C₆)alkyl, tetrahydropyridinyl(C₁-C₆)alkyl,thiophenyl(C₁-C₆)alkyl, phenylthio(C₁-C₆)alkyl, or pyridyl(C₁-C₆)alkyl,wherein each of the above is unsubstituted or substituted with 1, 2, or3 groups that are independently (C-C₁ ₋ ₄)alkyl, fluoro, chloro, bromo,(C₁-C₄)alkoxy, phenyl(C₁-C₄)alkoxy, thio (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, phenyl(C₁-C₄)alkoxycarbonyl, CO₂H, CN,amidinooxime, NR₆R₇, NR₆R₇alkyl, —C(O)NR₆R₇, amidino, CF₃, —CF₂CF₃, OCF₃or OCF₂CF₃.
 9. A compound or salt according to claim 8 wherein R₁ ishalogen, (Cl-C₄)alkanoyl, phenyl(C₁-C₄)alkanoyl, benzyl, phenethyl,phenpropyl, hydroxyalkyl, or carboxaldehyde, wherein the above phenylgroups are unsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro/CN, CF₃, OCF₃ orCO₂H; the alkyl portion of the above groups are unsubstituted orsubstituted with 1, 2, or 3 groups that are independently halogen,methoxy, or ethoxy; R₂ is benzyloxy, phenethyloxy, phenpropyloxy,phenbutyloxy, phenyloxy, OH, halogen, phenylthioalkoxy, alkoxy, alkyl,alkoxyalkoxy, wherein n is 0, 1, 2, 3, or 4, and the above groups areunsubstituted or substituted with 1, 2, or 3, groups that areindependently halogen, halo(C₁-C₄)alkyl, or thiophenyl; R₃ is halogen,phenylalkoxycarbonyl, phenyloxycarbonyl, phenyl(C₁-C₆)alkyl,phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy,(C₂-C₆)alkenyl, NR₆R₇ or alkyl, wherein the above phenyl groups areunsubstituted or substituted with 1, 2, or 3 groups that areindependently, halogen, alkoxy, (C₁-C₄)alkyl, CF₃, or OCF₃, R₄ is H,(C_(1 -C) ₆)alkyl, phenylalkoxy, benzyl, phenethyl, hydroxyalkyl,haloalkyl, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl portion ofthe above groups are unsubstituted or substituted with 1, 2, or 3 groupsthat are independently halogen, hydroxy, (C₁-C₄)alkoxy₁ (C₁-C₄)alkyl,nitro, CF₃, or OCF₃. R₅ is benzyl, phenethyl, phenpropyl, phenbutyl,(C₁-C₆)alkyl, phenyl, or pyridyl, wherein each of the above isunsubstituted or substituted with 1, 2, or 3 groups that areindependently (C₁-C₄)alkyl, fluoro, chloro, bromo, (C₁-C₄)alkoxy,phenyl(C₁-C₄)alkoxy, thio (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, CO₂H,CN, amidinooxime, NR₆R₇, amidino, CF₃, or OCF₃.
 10. A compound or saltaccording to claim 9 wherein R₁ is bromo, phenyl(C_(1 -C) ₄)alkanoyl,benzyl, phenethyl, phenpropyl, hydroxyalkyl, or carboxaldehyde, whereinthe above phenyl groups are unsubstituted or substituted with 1, 2, or 3groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro,CN, CF₃, OCF₃ or CO₂H; R₂ is benzyloxy, phenethyloxy, phenpropyloxy,phenbutyloxy, phenyloxy, OH, halogen, ro phenylthioalkoxy, wherein n is0, 1, 2, 3, or 4, and the above groups are unsubstituted or substitutedwith 1, 2, or 3, groups that are independently halogen,halo(C₁-C₄)alkyl, or thiophenyl; R₃ is bromo, phenylalkoxycarbonyl,phenyloxycarbonyl, phenyl(C_(1 -C) ₆)alkyl, phenylalkoxy, phenyloxy,phenylthio, thioalkoxy, phenylthioalkoxy, (C₂-C₆)alkenyl, NR₆R₇ oralkyl, wherein the above phenyl groups are unsubstituted or substitutedwith 1, 2, or 3 groups that are independently, halogen, alkoxy,(C₁-C₄)alkyl, CF₃, or OCF₃, R₄ is H, (C₁-C₆)alkyl, phenylalkoxy, benzyl,or phenethyl, wherein the phenyl portion of the above groups areunsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, hydroxy, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, nitro, CF₃,or OCF₃. R₅ is benzyl, phenethyl, phenpropyl, (C₁-C₆)alkyl, phenyl, orpyridyl, wherein each of the above is unsubstituted or substituted with1, 2, or 3 groups that are independently (C₁-C₄)alkyl, fluoro, chloro,bromo, (C₁-C₄)alkoxy, CO₂H, CN, amidinooxime, amidino, CF₃, or OCF₃. 11.A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein R₁ is H, halogen,alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy, arylalkyl, CN,alkanoyl, alkoxy, alkoxyalkyl, or arylalkanoyl, wherein the aryl portionof arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted orsubstituted with 1, 2, 3, 4,or 5 groups that are independently halogen,C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂H;wherein the alkyl portion of the alkyl, hydroxyalkyl, arylalkoxy,arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups isunsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, methoxy, ethoxy or spirocyclopropyl; R₂ is H,arylthio, —OC(O)NH(CH₂)_(n)aryl, arylalkyl, —OC(O)N(alkyl)(CH₂)_(n)aryl, or arylthioalkoxy, wherein n is 1, 2, 3, 4, or 5; R₃ ishalogen, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl,—OC(O)NH(CH₂)_(n)aryl, arylalkoxy, —OC(O)N(alkyl) (CH₂)_(n)aryl,aryloxy, arylthio, thioalkoxy, arylthioalkoxy, alkenyl, NR₆R₇ or alkyl,wherein the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl,arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy, —OC(O)N(alkyl)(CH₂)_(n)aryl, and arylthioalkoxy, is unsubstituted or substituted with1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl,haloalkyl, or haloalkoxy, wherein n is 0, 1, 2, 3, 4, S, or 6; or R₄ isH, alkyl, arylalkoxy, arylalkyl, hydroxyalkyl, haloalkyl, NR₆R₇alkyl,alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein The aryl portion ofarylalkoxy, arylalkyl is unsubstituted or substituted with 1, 2, 3, 4,or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl,nitro, haloalkyl, or haloalkoxy; and R₅ is arylalkyl, alkyl, aryl,alkoxy, heterocycloalkylalkyl, heteroarylalkyl, arylthioalkyl,heterocycloalkyl, or heteroaryl, wherein each of the above isunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy,alkoxycarbonyl, arylalkoxycarbonyl, CO₂H, CN, amidinooxime, NR₆R₇,NR₆R₇alkyl, —C(O)NR₆R₇, amidino, haloalkyl, or haloalkoxy.
 12. Acompound or salt according to claim 11 wherein R₁ is H, F, Cl, Br,(C₁-C₆)alkyl, carboxaldehyde, hydroxy(C₁-C₆)alkyl, phenyl(C_(1 -C)₆)alkoxy, phenyl(C₁-C₆)alkyl, CN, or phenyl(C₁-C₆)alkanoyl wherein thephenyl portion of the above is unsubstituted or substituted with 1, 2,or 3 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy,nitro, CN, haloalkyl, haloalkoxy or CO₂H; wherein the alkyl portion ofabove is unsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, methoxy, or ethoxy.
 13. A compound or saltaccording to claim 11 wherein R₂ is H, phenylthio,—OC(O)NH(CH₂)_(n)aryl, phenylalkyl, —OC(O)N(alkyl) (CH₂)_(n)aryl, orphenylthio(C₁-C₆)alkoxy, wherein n is 1, 2, 3, or
 4. 14. A compound orsalt according to claim 11 wherein R₃ is halogen, alkoxycarbonyl,phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl,—OC(O)NH(CH₂)_(n)phenyl, phenylalkoxy, —OC(O)N(alkyl) (CH₂)_(n)phenyl,phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR₆R₇ oralkyl, wherein the phenyl portion of the above is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently, halogen,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, or halo(C₁-C₄)alkoxy,wherein n is 0, 1, 2, 3, or
 4. 15. A compound or salt according to claim11 wherein R₄ is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl,haloalkyl, NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein thephenyl portion of phenylalkoxy, phenylalkyl is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently halogen,hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy.
 16. A compoundor salt according to claim 11 wherein R₅ is benzyl, phenethyl,phenpropyl, phenbutyl, alkyl, phenyl, alkoxy, pyridyl(C₁-C₆)alkyl,phenyl(C₁-C₆) thioalkyl, pyrrolyl, pyrrolyl(C₁-C₆)alkyl, or pyridyl,wherein each of the above is unsubstituted or substituted with 1, 2, or3 groups that are independently (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy,phenyl(C₁-C₆)alkoxy, (C₁-C₆) thioalkoxy, alkoxycarbonyl, CO₂H, CN,amidinooxime, amidino, CF₃, or OCF₃.
 17. A compound or salt according toclaim 11 wherein R₁ is H, Cl, Br, (C₁-C₆)alky, carboxaldehyde,hydroxy(C₁-C₆)alkyl, wherein the alkyl portion of above is unsubstitutedor substituted with 1, 2, or 3 groups that are independently halogen,methoxy, or ethoxy R₂ is H, phenylthio, —OC(O)NH(CH₂)_(n)aryl,phenylalkyl, —OC(O)N(alkyl) (CH₂)_(n)aryl, or phenylthio(C₁-C₆)alkoxy,wherein n is 1, 2, 3, or 4 R₃ is bromo, alkoxycarbonyl,phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl, phenylalkoxy,phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR₆R₇ oralkyl, wherein the phenyl portion of the above is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently, halogen,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, or halo(C₁-C₄)alkoxy,wherein n is 0, 1, 2, 3, or 4; R₄ is H, alkyl, phenylalkoxy,phenylalkyl, hydroxyalkyl, haloalkyl, NR₆R₇alkyl, alkoxy, alkoxyalkyl,or wherein the phenyl portion of phenylalkoxy, phenylalkyl isunsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, orhaloalkoxy R₅ is benzyl, phenethyl, phenpropyl, phenbutyl, alkyl,phenyl, phenyl(CI-C₆)thioalkyl, pyrrolyl, or pyridyl, wherein each ofthe above is unsubstituted or substituted with 1, 2, or 3 groups thatare independently (C₁-C₅)alkyl, halogen, (C₁-C₆)alkoxy, benzyloxy,(C₁-C₆)thioalkoxy, alkoxycarbonyl, CO₂H, CN, amidinooxime, amidino, CF₃,or OCF₃.
 18. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein R₁ is H, halogen,alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy, arylalkyl, CN,alkanoyl, alkoxy, alkoxyalkyl, or arylalkanoyl, wherein the aryl portionof arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted orsubstituted with 1, 2, 3, 4, or 5 groups that are independently halogen,C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂H;wherein the alkyl portion of the alkyl, hydroxyalkyl, arylalkoxy,arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups isunsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, methoxy, ethoxy or spirocyclopropyl; R₂ isarylalkoxy, aryloxy, OH, halogen, arylthioalkoxy, alkoxy,—OC(O)NH(CH₂)_(n)aryl, —OC(O)N(alkyl) (CH₂)_(n)aryl, alkyl,alkoxyalkoxy, dialkylamino, or CO₂H, wherein N is 0, 1, 2, 3, 4, 5 or 6;the aryl portion of arylalkoxy, aryloxy, arylthioalkoxy,OC(O)NH(CH₂)_(n)aryl, and —OC(O)N(alkyl) (CH₂)_(n)aryl or the heteroaryland heterocycloalkyl groups is unsubstituted or substituted with 1, 2,3, 4, or 5 groups that are independently halogen, haloalkyl, heteroaryl,heteroarylalkyl, NR₆R₇, NR₆R₇alkyl, —OC(O)NR₆R₇, wherein R₆ and R₇ areindependently at each occurrence H, alkyl, alkoxy, alkanoyl, arylalkyl,arylalkoxy, or arylalkanoyl, wherein the aryl portion of arylalkyl,arylalkoxy, or arylalkanoyl is unsubstituted or substituted with 1, 2,or 3 groups that are independently, halogen, alkoxy, alkyl, haloalkyl,or haloalkoxy; R₃ is halogen, alkoxycarbonyl, arylalkoxycarbonyl,aryloxycarbonyl, arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy,—OC(O)N(alkyl) (CH₂)_(n)aryl, aryloxy, arylthio, thioalkoxy,arylthioalkoxy, alkenyl, NR₆R₇ or alkyl, wherein the aryl portion ofarylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, —OC(O)NH(CH₂)_(n)aryl,arylalkoxy, —OC(O)N(alkyl) (CH₂)_(n)aryl, and arylthioalkoxy, isunsubstituted or substituted with 1, 2, or 3 groups that areindependently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy, whereinn is 0, 1, 2, 3, 4, 5, or 6; or R₂, R₃ and the carbons to which they areattached form an aryl, heterocycloalkyl or a heteroaryl ring, which isunsubstituted or substituted with 1, 2, or 3 groups that areindependently alkyl, alkoxy, halogen, arylalkyl, arylalkoxy,heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂, haloalkyl, orhaloalkoxy; R₄ is H, alkyl, arylalkoxy, arylalkyl, hydroxyalkyl,haloalkyl, NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein Thearyl portion of arylalkoxy, arylalkyl is unsubstituted or substitutedwith 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy,alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and R₅ is aryl,heterocycloalkylalkyl, heteroarylalkyl, arylthioalkyl, heterocycloalkyl,or heteroaryl, wherein each of the above is unsubstituted or substitutedwith 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen,alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl,CO₂H, CN, amidinooxime, NR₆R₇, NR₆R₇alkyl, —C(O)NR₆R₇, amidino,haloalkyl, or haloalkoxy.
 19. A compound or salt according to claim 18wherein R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl,phenylalkoxy, phenylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl, orphenylalkanoyl, wherein the above phenyl groups are unsubstituted orsubstituted with 1, 2, 3, 4, or 5 groups that are independently halogen,C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂H;wherein the alkyl portion of the alkyl, hydroxyalkyl, arylalkoxy,arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups isunsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, methoxy, ethoxy or spirocyclopropyl; R₂ isphenylalkoxy, phenyloxy, OH, halogen, phenylthioalkoxy, alkoxy,—OC(O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl) (CH₂)_(n)phenyl, alkyl,alkoxyalkoxy, dialkylamino, or CO₂H, wherein n is 0, 1, 2, 3, 4, 5 or 6;the above aryl groups are unsubstituted or substituted with 1, 2, 3, 4,or 5 groups that are independently halogen, haloalkyl, pyridyl,thiophenyl, NR₆R₇, NR₆R₇alkyl, or —OC(O)NR₆R₇, wherein R₆ and R₇ areindependently at each occurrence H, alkyl, alkoxy, alkanoyl,phenylalkyl, phenylalkoxy, or phenylalkanoyl, wherein the phenyl portionof the above is unsubstituted or substituted with 1, 2, or 3 groups thatare independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy. 20.A compound or salt according to claim 18 wherein R₃ is halogen,alkoxycarbonyl, phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl,—OC(O)NH(CH₂)_(n)phenyl, phenylalkoxy, —OC(O)N(alkyl) (CH₂)_(n),phenyl,phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR₆R₇ oralkyl, wherein the phenyl portion of the above is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently, halogen,alkoxy, alkyl, haloalkyl, or haloalkoxy, wherein n is 0, 1, 2, 3, 4, 5,or 6; or R₂, R₃ and the carbons to which they are attached form anphenyl, piperidinyl, pyrrolyl, pyrrolinyl or a pyridyl ring, each ofwhich is unsubstituted or substituted with 1, 2, or 3 groups that areindependently alkyl, alkoxy, halogen, phenylalkyl, phenylalkoxy, CN,NO₂, haloalkyl, or haloalkoxy; R₄ is H, alkyl, phenylalkoxy,phenylalkyl, hydroxyalkyl, haloalkyl, NR₆R₇alkyl, alkoxy, alkoxyalkyl,or alkoxyalkoxy, wherein the phenyl portion of the above isunsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, orhaloalkoxy; and R₅ is phenyl, naphthyl, pyrrolylalkyl, piperidinylalkylpyridinylalkyl, pyrimidinylalkyl, phenylthioalkyl, pyrrolyl,piperidinyl, pyridyl, or thiophenylalkyl, wherein each of the above isunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy,alkoxycarbonyl, phenylalkoxycarbonyl, CO₂H, CN, amidinooxime, NR₆R₇,NR₆R₇alkyl, —C(O)NR₆R₇, amidino, haloalkyl, or haloalkoxy.
 21. Acompound or salt according to claim 18 wherein R₁ is H, halogen, alkyl,carboxaldehyde, hydroxyalkyl, benzyloxy, phenethyloxy, phenpropyloxy,benzyl, phenethyl, phenpropyl, CN, alkanoyl, alkoxy, or phenylC(O)—,phenylCH₂C(O)—, or phenylCH₂CH₂C(O), wherein the above phenyl groups areunsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN, CF₃, OCF₃or CO₂H; wherein the above alkyl groups are unsubstituted or substitutedwith 1, 2, or 3 groups that,-are independently halogen, methoxy, orethoxy; R₂ is benzyloxy, phenethyloxy, phenpropyloxy, phenyloxy, OH,halogen, phenylthioalkoxy, alkyl, alkoxy, —OC(O)NH(CH₂)_(n)phenyl,—OC(O)N(alkyl) (CH₂)_(n)phenyl, dialkylamino, or CO₂H, wherein n is 0,1, 2, 3, or 4; the above aryl groups are unsubstituted or substitutedwith 1, 2, 3, 4, or 5 groups that are independently halogen, CF₃,pyridyl, thiophenyl, NR₆R₇, or NR₆R₇alkyl, wherein R₆ and R₇ areindependently at each occurrence H, alkyl, alkanoyl, benzyl, orphenylC(O)—, wherein the phenyl portion of the above is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently, halogen,alkoxy, alkyl, CF₃, or OCF₃; R₃ is halogen, alkoxycarbonyl,phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl,—OC(O)NH(CH₂)_(n)phenyl, phenylalkoxy, —OC(O)N(alkyl) (CH₂)_(n)phenyl,phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR₆R₇ oralkyl, wherein the phenyl portion of the above is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently, halogen,alkoxy, alkyl, haloalkyl, or haloalkoxy, wherein n is 0, 1, 2, 3,or 4;R₄ is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl,NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenylportion of the above is unsubstituted or substituted with 1, 2, or 3groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro,haloalkyl, or haloalkoxy; and R₅ is phenyl, naphthyl, pyrrolylalkyl,piperidinylalkyl pyridinylalkyl, pyrimidinylalkyl, phenylthioalkyl,pyrrolyl, piperidinyl, pyridyl, or thiophenylalkyl, wherein each of theabove is unsubstituted or substituted with 1, 2, or 3 groups that areindependently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy,alkoxycarbonyl, phenylalkoxycarbonyl, CO₂H, CN, amidinooxime, NR₆R₇,NR₆R₇alkyl, —C(O)NR₆R₇, amidino, haloalkyl, or haloalkoxy.
 22. Acompound or salt according to claim 21 wherein R₁ is H, halogen, alkyl,carboxaldehyde, hydroxyalkyl, benzyloxy, phenethyloxy, benzyl,phenethyl, CN, (C₁-C₆)alkanoyl, alkoxy, or phenylC(O)—, orphenylCH₂C(O)—, wherein the above phenyl groups are unsubstituted orsubstituted with 1, 2, or 3 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H; R₂ is benzyloxy,phenethyloxy, phenpropyloxy, phenyloxy, OH, halogen, phenyl(C₁-C₄)thioalkoxy, —OC(O)NH(CH₂)_(n),phenyl, OC(O)N(alkyl) (CH₂)_(n)phenyl, ordialkylamino, wherein n is 0, 1, 2, 3, or 4; the above aryl groups areunsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, CF₃, NR₆R₇, or NR₆R₇alkyl, wherein R₆ and R₇ areindependently at each occurrence H, (C₁-C₆)alkyl, acetyl, benzyl, orphenylC(O)—, wherein the phenyl portion of the above is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently, halogen,alkoxy, alkyl, CF₃, or OCF₃; R₃ is halogen, alkoxycarbonyl,phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl, phenylalkoxy,phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR₆R₇ oralkyl, wherein the phenyl portion of the above is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently, halogen,alkoxy, alkyl, haloalkyl, or haloalkoxy, wherein n is 0, 1, 2, 3,or 4;R₄ is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl,NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenylportion of the above is unsubstituted or substituted with 1, 2, or 3groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro,haloalkyl, or haloalkoxy; and R₅ is phenyl, phenyl(C₁-C₄)thioalkyl,pyridyl, or thiophenyl(C₁-C₄)alkyl, wherein each of the above isunsubstituted or substituted with 1, 2, or 3 groups that areindependently (C₁-C₄)alkyl, fluoro, chloro, bromo, (C₁-C₄)alkoxy, CN,amidinooxime, amidino, CF₃, or OCF₃.
 23. A compound or salt according toclaim 22 wherein R₅ is substituted with at least one group selected fromfluoro, chloro, bromo, and methyl.
 24. A pharmaceutical compositioncomprising at least one pharmaceutically acceptable carrier, solvent,adjuvant or excipient and a compound or salt according to claim
 2. 25. Apharmaceutical composition comprising at least one pharmaceuticallyacceptable carrier, solvent, adjuvant or excipient and a compound orsalt according to claim
 11. 26. A pharmaceutical composition comprisingat least one pharmaceutically acceptable carrier, solvent, adjuvant orexcipient and a compound or salt according to claim
 18. 27. A compoundof the formula:

or a pharmaceutically acceptable salt thereof, wherein R₁ is H, halogen,alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy, arylalkyl, alkenyl,alkynyl, arylalkynyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, orarylalkanoyl, wherein the aryl portion of arylalkoxy, arylalkyl, andarylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro,CN, haloalkyl, haloalkoxy or CO₂H; wherein the alkyl portion of thealkyl, hydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy,alkoxyalkyl and arylalkanoyl groups is unsubstituted or substituted with1, 2, or 3 groups that are independently halogen, methoxy, ethoxy orspirocyclopropyl; R₂ is arylalkoxy, aryloxy, arylthioalkoxy, alkoxy,—OC(O)NH(CH₂)_(n)aryl, —OC(O)N(alkyl) (CH₂)_(n)aryl, alkyl,alkoxyalkoxy, dialkylamino, pyridyl, pyrimidyl, pyridazyl, pyrazolyl,imidazolyl, pyrrolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl,piperidinyl, hexahydropyrimidinyl, thiazolyl, thiophenyl, or CO₂H,wherein n is 0, 1, 2, 3, 4, 5 or 6; each of the above is unsubstitutedor substituted with 1, 2, 3, 4, or 5 groups that are independentlyhalogen, NR₆R₇, haloalkyl, haloalkoxy, alkyl, heteroaryl,heteroarylalkyl, NR₆R₇alkyl, —OC(O)NR₆R₇, wherein R₆ and R₇ areindependently at each occurrence H, alkyl, alkoxy, alkanoyl, arylalkyl,arylalkoxy, or arylalkanoyl, wherein the aryl portion of arylalkyl,arylalkoxy, or arylalkanoyl is unsubstituted or substituted with 1, 2,or 3 groups that are independently, halogen, alkoxy, alkyl, haloalkyl,or haloalkoxy; R₄ is H, alkyl, arylalkoxy, arylalkyl, hydroxyalkyl,haloalkyl, NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein thearyl portion of arylalkoxy, arylalkyl is unsubstituted or substitutedwith 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy,alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and R₅ is arylalkyl,alkyl, aryl, alkoxy, heterocycloalkylalkyl, heteroarylalkyl,heterocycloalkyl, or heteroaryl, wherein each of the above isunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy,alkoxycarbonyl, arylalkoxycarbonyl, CO₂H, CN, OH, amidinooxime, NR₈R₉,NR₆R₇alkyl, —C(O)NR₆R₇, amidino, haloalkyl, or haloalkoxy; wherein R₈ ishydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl; wherein R₅ isalkyl, alkanoyl, arylalkyl and arylalkanoyl; provided that when R₂ isbenzyloxy, and R₅ is benzyl or methyl, R₁ is not hydrogen.
 28. Acompound or salt according to claim 27 wherein R₁ is H, halogen, alkyl,carboxaldehyde, hydroxyalkyl, phenyl(C₁-C₆)alkoxy, phenyl(C-C₆)alkyl,CN, phenyl(C₂-C₆ alkynyl), C₂-C₆ alkynyl, alkanoyl, alkoxy, alkoxyalkyl,haloalkyl, or phenyl(C₁-C₆)alkanoyl, wherein the phenyl groups areunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN, haloalkyl,haloalkoxy or CO₂H; wherein the alkyl groups are unsubstituted orsubstituted with 1, 2, or 3 groups that are independently halogen,methoxy, ethoxy or spirocyclopropyl.
 29. A compound or salt according toclaim 27 wherein R₂ is phenyl(C₁-C₆)alkoxy, phenyloxy, phenylthioalkoxy,C₁-C₈ alkoxy, alkyl, alkoxyalkoxy, —OC(O)NH (CH2)_(n)phenyl,—OC(O)N(alkyl) (CH₂)_(n)phenyl, dialkylamino, pyridyl, pyrimidyl,pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl,triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl,thiazolyl, thiophenyl, or CO₂H, wherein n is 0, 1, 2, 3, 4, 5 or 6; eachof the above is unsubstituted or substituted with 1, 2, 3, 4, or 5groups that are independently halogen, NR₆R₇, haloalkyl, haloalkoxy,alkyl, heteroaryl, heteroarylalkyl, NR₆R₇alkyl, —OC(O)NR₆R₇, wherein R₆and R₇ are independently at each occurrence H, alkyl, alkoxy, alkanoyl,arylalkyl, arylalkoxy, or arylalkanoyl, wherein the aryl portion ofarylalkyl, arylalkoxy, or arylalkanoyl is unsubstituted or substitutedwith 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl,haloalkyl, or haloalkoxy.
 30. A compound or salt according to claim 27wherein R₄ is H, (C₁-C₆)alkyl, phenyl(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkyl,hydroxyalkyl, haloalkyl-, NR₆R₇alkyl, alkoxy, alkoxyalkyl, oralkoxyalkoxy, wherein the phenyl groups are unsubstituted or substitutedwith 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy,alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy.
 31. A compound or saltaccording to claim 27 wherein R₅ is phenyl(C₁-C₆)alkyl, (C₁-C₆)alkyl,phenyl, alkoxy, heterocycloalkylalkyl, naphthyl(C₁-C₆)alkyl,heteroarylalkyl, heterocycloalkyl, or heteroaryl, wherein each of theabove is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups thatare independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy,alkoxycarbonyl, CO₂H, CN, amidinooxime, NR₈R₉, NR₆R₇alkyl, —C(O)NR₆R₇,amidino, haloalkyl, or haloalkoxy; wherein R₈ is hydrogen, alkyl,alkanoyl, arylalkyl and arylalkanoyl; wherein R₉ is alkyl, alkanoyl,arylalkyl and arylalkanoyl; provided that when R₂ is benzyloxy, and R₅is benzyl or methyl, R, is not hydrogen.
 32. A compound or saltaccording to claim 27 wherein R₁ is H, halogen, alkyl, carboxaldehyde,hydroxyalkyl, phenyl(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkyl, CN, alkanoyl,alkoxy, ethynyl, alkoxyalkyl, haloalkyl, or phenyl(C₁-C₆)alkanoyl,wherein the phenyl groups are unsubstituted or substituted with 1, 2, 3,4, or 5 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H; wherein the alkyl groups areunsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, methoxy, or ethoxy; R₂ is phenyl(C₁-C₆)alkoxy,phenyloxy, phenylthioalkoxy, C₁-C₈ alkoxy, alkyl, alkoxyalkoxy,—OC(O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl) (CH₂)_(n)phenyl, dialkylamino,pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl,benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl,hexahydropyrimidinyl, thiazolyl, thiophenyl, or CO₂H, wherein n is 0, 1,2, 3, 4, 5 or 6; each of the above is unsubstituted or substituted with1, 2, 3, 4, or 5 groups that are independently halogen, NR₆R₇,haloalkyl, haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, NR₆R₇alkyl,—OC(O)NR₆R₇, wherein R₆ and R₇ are independently at each occurrence H,alkyl, alkoxy, alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl, whereinthe aryl portion of arylalkyl, arylalkoxy, or arylalkanoyl isunsubstituted or substituted with 1, 2, or 3 groups that areindependently, halogen, alkoxy, alkyl, CF₃, OCF₃; R₄ is H, (C₁-C₆)alkyl,phenyl(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkyl, hydroxyalkyl, haloalkyl,NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenylgroups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groupsthat are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3 ,OCF₃; and R₅ is phenyl(C₁-C₆)alkyl, (C₁-C₆)alkyl, phenyl, alkoxy,piperidinylalkyl, thienylalkyl, naphthyl(C₁-C₆)alkyl, heteroarylalkyl,heterocycloalkyl, or heteroaryl, wherein each of the above isunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy,alkoxycarbonyl, CO₂H, CN, amidinooxime, NR₈R₉, NR₆R₇alkyl, —C(O)NR₆R₇,amidino, CF₃, or OCF₃; wherein R₈ is hydrogen, alkyl, alkanoyl,arylalkyl and arylalkanoyl; wherein R₉ is alkyl, alkanoyl, arylalkyl andarylalkanoyl; provided that when R₂ is benzyloxy, and R₅ is benzyl ormethyl, R₁ is not hydrogen.
 33. A compound or salt according to claim 32wherein R₁ is H, halogen), alkyl, haloalkyl, carboxaldehyde,hydroxyalkyl, phenyl(C₁-C₆)alkoxy, benzyl, phenethyl, phenpropyl, CN, orphenyl(C₁-C₆)alkanoyl, wherein the phenyl groups are unsubstituted orsubstituted with 1, 2, or 3 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H; R₂ is benzyloxy,phenyloxy, phenylthioalkoxy, C₁-C₈, —OC(O)NH(CH₂)_(n)phenyl,—OC(O)N(alkyl) (CH₂)_(n)phenyl, dialkylamino, pyridyl, pyrimidyl,pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl,triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl,thiazolyl, thiophenyl, or CO₂H, wherein n is 0, 1, 2, 3, 4, 5 or 6; eachof the above is unsubstituted or substituted with 1, 2, 3, 4, or 5groups that are independently halogen, NR₆R₇, haloalkyl, haloalkoxy,alkyl, heteroaryl, or NR₆R₇alkyl, wherein R₆ and R₇ are independently ateach occurrence H, alkyl, alkoxy, alkanoyl, arylalkyl, arylalkoxy, orarylalkanoyl, wherein the aryl portion of arylalkyl, arylalkoxy, orarylalkanoyl is unsubstituted or substituted with 1, 2, or 3 groups thatare independently, halogen, alkoxy, alkyl, CF₃, OCF₃; R₄ is H,(C₁-C₆)alkyl, phenyl(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkyl, hydroxyalkyl,wherein the phenyl groups are unsubstituted or substituted with 1, 2, 3,4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl,nitro, CF₃, OCF₃; and R₅ is phenyl(C₁-C₆)alkyl, (C₁-C₆)alkyl, phenyl,piperidinylalkyl, thienylalkyl, heteroaryl, naphthyl(C₁-C₆)alkyl,heteroarylalkyl, or wherein each of the above is unsubstituted orsubstituted with 1, 2, 3, 4, or 5 groups that are independently alkyl,halogen, alkoxy, benzyloxy, thioalkoxy, —CO₂CH₃, —CO₂CH₂CH₃, —CO2(C₃-C₅alkyl), CO₂H, CN, amidinooxime, NR₈R₉, NR₆R₇alkyl, —C(O)NR₆R₇, amidino,CF₃, or OCF₃; wherein R₈ is hydrogen, alkyl, alkanoyl, arylalkyl andarylalkanoyl; wherein R₉ is alkyl, alkanoyl, arylalkyl and arylalkanoyl;provided that when R₂ is benzyloxy, and R₅ is benzyl or methyl, R₁ isnot hydrogen.
 34. A compound or salt according to claim 33 wherein R₁ isH, halogen, alkyl or carboxaldehyde; R₂ is benzyloxy, phenyloxy,phenylthioalkoxy, or pyridyl; wherein each of the above is unsubstitutedor substituted with 1, 2, or 3, groups that are independently halogen,haloalkyl, or alkyl.
 35. A compound or salt according to claim 33wherein R₄ is H, (C₁-C₄)alkyl, phenyl(C₁-C₆)alkoxy, benzyl, phenyethyl,phenpropyl, hydroxy(C₁-C₆)alkyl, wherein the phenyl groups areunsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, hydroxy, alkoxy, alkyl, nitro, CF₃, OCF₃; and R₅is benzyl, phenethyl, phenpropyl, phenbutyl, (C₁-C₆)alkyl, phenyl,pyridyl, pyrimidyl, naphthyl(C₁-C₆)alkyl, thiophenyl(C₁-C₆)alkyl, orpyridyl(C₁-C₆)alkyl wherein each of the above is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently alkyl,halogen, alkoxy, benzyloxy, thioalkoxy, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂(C₃-C₅alkyl), CF₃, OCF₃, CO₂H, CN, amidinooxime; provided that when R₂ isbenzyloxy, and R₅ is benzyl or methyl, R₁ is not hydrogen.
 36. Acompound or salt according to claim 33 wherein R₁ is bromo, iodo, or H;and R₅ is benzyl, phenethyl, phenpropyl, phenyl, piperidinylalkyl,thienylalkyl, -CH₂-pyridyl, or pyridyl, each of which is unsubstitutedor substituted with 1, 2, or 3 groups that are independently C₁-C₄alkyl, halogen, CF₃, OCF₃, —CO₂CH₃, C₁-C₄ alkoxy, —CO₂CH₃, —CO₂CH₂CH₃,-QO2 (C₃-C₅ alkyl), benzyloxy, and amidinooxime.
 37. A compound or saltaccording to claim 36 wherein R₂ is benzyloxy, or phenethyloxy; each ofthe above is unsubstituted or substituted with 1, 2, or 3, groups thatare independently fluoro, chloro, bromo, CF₃, or (C₁-C₄)alkyl.
 38. Acompound of the formula

or a pharmaceutically acceptable salt thereof, wherein R₁ is halogen,alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy, arylalkyl, CN, aryl,alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, or arylalkanoyl, wherein thearyl portion of arylalkoxy, arylalkyl, and arylalkanoyl is unsubstitutedor substituted with 1, 2, 3, 4, or 5 groups that are independentlyhalogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, nitro, CN, haloalkyl, haloalkoxyor CO₂H; wherein the alkyl portion of the alkyl, hydroxyalkyl,arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoylgroups is unsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, methoxy, ethoxy or spirocyclopropyl; R₂ isarylalkoxy, arylalkyl, OH, aryloxy, arylthioalkoxy, alkoxy,—OC(O)NH(CH₂)_(n)aryl, —OC(O)N(alkyl) (CH₂)_(n)aryl, alkyl,alkoxyalkoxy, NR₆R₇, pyridyl, pyrimidyl, pyridazyl, pyrazolyl,imidazolyl, pyrrolyl, tetrahydroquinolinyl, amino,tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl,triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl,thiazolyl, thiophenyl, or CO₂H, wherein n is 0, 1, 2, 3, 4, 5 or 6; eachof the above is unsubstituted or substituted with 1, 2, 3, 4, or 5groups that are independently halogen, NR₆R₇, haloalkyl, haloalkoxy,alkyl, heteroaryl, heteroarylalkyl, NR₆R₇alkyl, —SO₂-phenyl wherein thephenyl is optionally substituted with 1 or 2 groups that are halogen orNO₂; or —OC(O)NR₆R₇₁ wherein R₆ and R₇ are independently at eachoccurrence H, alkyl, alkoxy, alkanoyl, arylalkyl, arylalkoxy, orarylalkanoyl, wherein the aryl portion of each of the above isunsubstituted or substituted with 1, 2, or 3 groups that areindependently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy; R₄ isH, alkyl, arylalkoxy, arylalkyl, hydroxyalkyl, haloalkyl, NR₆R₇alkyl,alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the aryl portion ofarylalkoxy, arylalkyl is unsubstituted or substituted with 1, 2, 3, 4,or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl,nitro, haloalkyl, or haloalkoxy; and R₅ is arylalkyl, alkyl, aryl,alkoxy, heterocycloalkylalkyl, heteroarylalkyl, heterocycloalkyl, orheteroaryl, wherein each of the above is unsubstituted or substitutedwith 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen,alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, OH,CO₂H, CN, amidinooxime, NR₈R₉, NR₆R₇alkyl, —C(O)NR₆R₇, amidino,haloalkyl, or haloalkoxy; wherein R₅ is hydrogen, alkyl, alkanoyl,arylalkyl and arylalkanoyl; and wherein R₉ is alkyl, alkanoyl, arylalkyland arylalkanoyl; provided that when R₂ is OH, R₄ is methyl and R₅ isphenyl, R₁ is not acetyl.
 39. A compound or salt according to claim 38wherein R₁ is halogen, alkyl, carboxaldehyde, hydroxyalkyl,phenylalkoxy, phenylalkyl, CN, alkanoyl, phenyl, alkoxy, alkoxyalkyl,haloalkyl, or phenylalkanoyl, wherein the above phenyl groups areunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, nitro, CN,haloalkyl, haloalkoxy or CO₂H; wherein the above alkyl groups areunsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, methoxy, or ethoxy.
 40. A compound or saltaccording to claim 38 wherein R₂ is phenylalkoxy, OH, phenyloxy,phenylthioalkoxy, alkoxy, —OC(O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl) (CH₂)phenyl, NR₆R₇, alkyl, dialkylamino, pyridyl, pyrimidyl, pyridazyl,pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl, amino,tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl,phenyl(C₁-C₆ alkyl), triazinyl, tetrahydrofuryl, piperidinyl,hexahydropyrimidinyl, thiazolyl, thiophenyl, or CO₂H, wherein n is 0, 1,2, 3, 4, 5 or 6; each of the above is unsubstituted or substituted with1, 2, 3, 4, or 5 groups that are independently halogen, NR₆R₇,haloalkyl, haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, orNR₆R₇alkyl, wherein R₆ and R₇ at each occurrence are independently H,alkyl, alkoxy, alkanoyl, phenylalkyl, phenylalkoxy, or phenylalkanoyl,wherein the above phenyl groups are unsubstituted or substituted with 1,2, or 3 groups that are independently, halogen, alkoxy, alkyl,haloalkyl, or haloalkoxy.
 41. A compound or salt according to claim 38wherein R₄ is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl,haloalkyl, NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein theabove phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro,haloalkyl, or haloalkoxy.
 42. A compound or salt according to claim 38wherein R₅ is phenylalkyl, (C₁-C₆)alkyl, phenyl, naphthyl, alkoxy,piperidinyl, pyrolidinyl, imidazolidinyl, piperazinyl,tetrahydropyranyl, piperidinyl(C₁-C₆)alkyl, pyrolidinyl(C₁-C₆)alkyl,imidazolidinyl(C₁-C₆)alkyl, piperazinyl(C₁-C₆)alkyl,tetrahydropyranyl(C₁-C₆)alkyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl,pyridyl(C₁-C₆)alkyl, pyrimidyl(C₁-C₆)alkyl, pyridazyl(C₁-C₆)alkyl, orpyrazinyl(C₁-C₆)alkyl wherein each of the above is unsubstituted orsubstituted with 1, 2, 3, 4, or 5 groups that are independently alkyl,halogen, alkoxy, phenylalkoxy, thioalkoxy, alkoxycarbonyl,phenylalkoxycarbonyl, OH, CO₂H, CN, amidinooxime, NR₈R₉, NR₆R₇alkyl,—C(O)NR₆R₇, amidino, haloalkyl, or haloalkoxy; wherein R₈ and R₉ areindependently hydrogen, alkyl, alkanoyl, phenylalkyl and phenylalkanoyl;provided that when R₂ is OH, R₄ is methyl and R₅ is phenyl, R₁ is notacetyl.
 43. A compound or salt according to claim 38 wherein R₁ ishalogen, alkyl, phenyl, carboxaldehyde, hydroxyalkyl, phenylalkoxy,phenylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, orphenylalkanoyl, wherein the above phenyl groups are unsubstituted orsubstituted with 1, 2, or 3 groups that are independently halogen,(C₁-C₄)alkyl, (C₁-C₄)alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂H;wherein the above alkyl groups are unsubstituted or substituted with 1,2, or 3 groups that are independently halogen, methoxy, or ethoxy, R₂ isphenylalkoxy, OH, phenyloxy, phenylthio(C₁-C₄)alkoxy, alkoxy, phenethyl,—OC(O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl) (CH₂)_(n)phenyl, alkyl,alkoxyalkoxy, NR₆R₇, pyridyl, pyrimidyl, pyridazyl, pyrazolyl,imidazolyl, pyrrolyl, tetrahydroquinolinyl, amino,tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl,triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl,thiazolyl, thiophenyl, or CO₂H, wherein n is 0, 1, 2, or 3; each of theabove is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups thatare independently halogen, haloalkyl, haloalkoxy, alkyl, thiophenyl, orpyridyl; R₆ and R₇ are independently at each occurrence H, alkyl,alkoxy, alkanoyl, benzyl, arylalkoxy, or arylalkanoyl, wherein the arylportion of each of the above is unsubstituted or substituted with 1, 2,or 3 groups that are independently, halogen, alkoxy, alkyl, CF₃, orOCF₃; R₄ is H, alkyl, phenylalkoxy, phenylalkyl, hydroxyalkyl,haloalkyl, NR₆R₇alkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein theabove phenyl groups are unsubstituted or substituted with 1, 2, or 3groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro,haloalkyl, or haloalkoxy; and R₅ is benzyl, phenethyl, (C₁-C₆)alkyl,phenyl, naphthyl, alkoxy, piperidinyl, pyrolidinyl, imidazolidinyl,piperazinyl, piperidinyl(C₁-C₆)alkyl, pyrolidinyl(C₁-C₆)alkyl,imidazolidinyl(C₁-C₆)alkyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl,pyridyl(C₁-C₆)alkyl, pyrimidyl(C₁-C₆)alkyl, pyridazyl(C₁-C₆)alkyl, orpyrazinyl(C₁-C₆)alkyl wherein each of the above is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently alkyl,halogen, alkoxy, phenylalkoxy, thioalkoxy, alkoxycarbonyl,phenylalkoxycarbonyl, OH, CO₂H, CN, amidinooxime, NR₈R₉, NR₆R₇alkyl,—C(O)NR₆R₇, amidino, haloalkyl, or haloalkoxy; wherein R₈ and R₉ areindependently hydrogen, alkyl, alkanoyl, phenylalkyl and phenylalkanoyl;provided that when R₂ is OH, R₄ is methyl and R₅ is phenyl, R₁ is notacetyl.
 44. A compound or salt according to claim 43 wherein R₁ ishalogen, alkyl, carboxaldehyde, hydroxyalkyl, phenylalkoxy, phenyl,benzyl, phenethyl, phenpropyl, phenbutyl, CN, (C₂-C₆)alkanoyl,haloalkyl, or phenylCO—, phenylCH₂CO—, phenylCH₂CH₂CO—, wherein theabove phenyl groups are unsubstituted or substituted with 1, 21 or 3groups that are independently halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,nitro, CN, haloalkyl, haloalkoxy or CO₂H; wherein the above alkyl groupsare unsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, methoxy, or ethoxy, R₂ is benzyloxy,phenethyloxy, phenpropyloxy, OH, phenyloxy, phenylthio(C₁-C₄)alkoxy,NR₆R₇, (C₁-C₆)alkyl, phenethyl, —OC(O)N(CH₃)CH₂phenyl, alkoxyalkoxy,pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl,pyrazinyl, piperidinyl, hexahydropyrimidinyl, benzimidazolyl, orthiophenyl, wherein each of the above is unsubstituted or substitutedwith 1, 2, or 3 groups that are independently halogen, CF₃, OCF₃,(C₁-C₄)alkyl, thiophenyl, or pyridyl; R₆ and R₇ are independently ateach occurrence H, alkyl, alkoxy, alkanoyl, phenylalkyl, phenylalkoxy,or phenylalkanoyl, wherein the phenyl portion of each of the above isunsubstituted or substituted with 1, 2, or 3 groups that areindependently, halogen, alkoxy, alkyl, CF₃, or OCF₃; R₄ is H, alkyl,benzyloxy, phenethyloxy, phenpropyloxy, benzyl, phenethyl, phenpropyl,hydroxyalkyl, halo (C₁-C₄)alkyl, NR₆R₇alkyl, alkoxy, alkoxyalkyl, oralkoxyalkoxy, wherein the above phenyl groups are unsubstituted orsubstituted with 1, 2, or 3 groups that are independently halogen,hydroxy, alkoxy, alkyl, nitro, CF₃ or OCF₃; and R₅ is benzyl, phenethyl,phenpropyl, phenbutyl, (C₁-C₆)alkyl, phenyl, piperidinyl, pyrolidinyl,imidazolidinyl, piperazinyl, piperidinyl(C₁-C₆)alkyl,pyrolidinyl(C_(1 -C) ₆)alkyl, imidazolidinyl(C₁-C₆)alkyl, pyridyl,pyrimidyl, pyridazyl, pyrazinyl, pyridyl(C₁-C₆)alkyl,pyrimidyl(C₁-C₆)alkyl, pyridazyl(C₁-C₆)alkyl, or pyrazinyl(C₁-C₆)alkylwherein each of the above is unsubstituted or substituted with 1, 2, or3 groups that are independently alkyl, halogen, alkoxy, benzyloxy,thioalkoxy, —CO₂CH₃, —CO₂CH₂CH₃, OH, CO₂H, CN, —CO₂(C₃-C₅ alkyl),phenylalkoxycarbonyl, amidinooxime, amidino, CF₃, CF₂CF₃, C₁CH₂, orOCF₃; provided that when R₂ is OH, R₄ is methyl and R₅ is phenyl, R₁ isnot acetyl.
 45. A compound or salt according to claim 44 wherein R₁ ishalogen, alkyl, carboxaldehyde, hydroxy(C₁-C₄)alkyl, phenylalkoxy,benzyl, phenethyl, —C(O)CH₃, phenylCO—, or phenylCH2CO—, wherein theabove phenyl groups are unsubstituted or substituted with 1, 2, or 3groups that are independently halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,nitro, CN, CF₃, or OCF₃; wherein the above alkyl groups areunsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, methoxy, or ethoxy; R₂ is benzyloxy,phenethyloxy, phenpropyloxy, OH, phenyloxy, NR₆R₇, —S-benzyl, or(C₁-C₆)alkyl, wherein each of the above is unsubstituted or substitutedwith 1, 2, or 3 groups that are independently halogen, CF₃, OCF₃, alkyl,thiophenyl, or pyridyl; R₆ and R₇ are independently at each occurrenceH, alkyl, alkanoyl, benzyl, benzyloxy, or phenylalkanoyl, wherein thephenyl portion of each of the above is unsubstituted or substituted with1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, CF₃,or OCF₃; R₄ is H, alkyl, benzyloxy, phenethyloxy, phenpropyloxy, benzyl,or hydroxyalkyl, wherein the above phenyl groups are unsubstituted orsubstituted with 1, 2, or 3 groups that are independently halogen,hydroxy, alkoxy, alkyl, nitro, CF₃ or OCF₃; and R₅ is benzyl, phenethyl,phenpropyl, phenbutyl, (C₁-C₆)alkyl, phenyl, pyridyl, orpyridyl(C₁-C₄)alkyl, wherein each of the above is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently alkyl,halogen, (C₁-C₄)alkoxy, phenyl(C₁-C₄)alkoxy, thio(C₁-C₄)alkoxy,alkoxycarbonyl, OH, CO₂H, CN, amidinooxime, amidino, CF₃, or OCF₃.
 46. Acompound or salt according to claim 45 wherein R₁ is halogen, alkyl,carboxaldehyde, or hydroxyalkyl; R₂ is benzyloxy, phenethyloxy,phenpropyloxy, OH, phenyloxy, phenylthioalkoxy, or (C₁-C₆)alkyl, whereineach of the above is unsubstituted or substituted with 1, 2, or 3 groupsthat are independently halogen, CF₃, OCF₃, alkyl, thiophenyl, orpyridyl; R₄ is H, (C₁-C₄)alkyl, benzyloxy, phenethyloxy, wherein theabove phenyl groups are unsubstituted or substituted with 1, 2, or 3groups that are independently halogen, hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkyl, nitro, CF₃ or OCF₃; and R₅ is benzyl, phenethyl,(C₁-C₆)alkyl, phenyl, or pyridyl, wherein each of the above isunsubstituted or substituted with 1, 2, or 3 groups that areindependently (C₁-C₄)alkyl, halogen, OH, CO₂H, CN, (C₁-C₄)alkoxy,benzyloxy, —CO₂CH₃, —CO2CH₂CH₃, —C₂(C₃-C₅ alkyl), amidino,thio(C₁-C₄)alkoxy, amidinooxime, CF₃, or OCF₃.
 47. A compound or saltaccording to claim 46 wherein R₁ is bromo; and R₅ is benzyl, phenethyl,phenpropyl, phenyl, or pyridyl, each of which is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently alkyl, OH,halogen, alkoxy, and amidinooxime.
 48. A compound or salt according toclaim 47 wherein R₂ is benzyloxy, or phenethyloxy, each of which isunsubstituted or substituted with 1, 2, or 3 groups that areindependently halogen, CF₃, OCF₃, or (C₁-C₄)alkyl.
 49. A pharmaceuticalcomposition comprising at least one pharmaceutically acceptable carrier,solvent, adjuvant or excipient and a compound or salt according to claim27.
 50. A pharmaceutical composition comprising at least onepharmaceutically acceptable carrier, solvent, adjuvant or excipient anda compound or salt according to claim
 38. 51. A method of treating a TNFmediated disorder, a p38 kinase mediated disorder, inflammation and/orarthritis in a subject, the method comprising treating a subject havingor susceptible to such disorder or condition with atherapeutically-effective amount of a compound or salt of any of thepreceding claims.
 52. A method according to claim 51 for treating orpreventing inflammation; arthritis, rheumatoid arthritis,spondylarthropathies, gouty arthritis, osteoarthritis, systemic lupuserthematosus, juvenile arthritis; neuroinflammation; pain, neuropathicpain; fever; pulmonary disorders, lung inflammation, adult respiratorydistress syndrome, pulmonary sarcoisosis, asthma, silicosis, chronicpulmonary inflammatory disease; cardiovascular disease,arteriosclerosis, myocardial infarction, thrombosis, congestive heartfailure, cardiac reperfusion injury; cardiomyopathy; reperfusion injury;renal reperfusion injury; ischemia including stroke and brain ischemia;brain trauma; brain edema; liver disease and nephritis; gastrointestinalconditions, inflammatory bowel disease, Crohn's disease, gastritis,irritable bowel syndrome, ulcerative colitis; ulceratiuve diseases,gastric ulcers; ophthalmic diseases, retinitis, retinopathies, uveitis,ocular photophobia, acute injury to the eye tissue; ophthalmologicalconditions, corneal graft rejection, ocular neovascularization, retinalneovascularization, neovascularization following injury or infection,diabetic retinopathy, retrolental fibroplasias, neovascular glaucoma;diabetes; diabetic nephropathy; skin-related conditions, psoriasis,eczema, burns, dermatitis, keloid formation, scar tissue formation,angiogenic disorders; viral and bacterial infections, sepsis, septicshock, gram negative sepsis, malaria, meningitis, opportunisticinfections, cachexia secondary to infection or malignancy, cachexiasecondary to acquired immune deficiency syndrome, (AIDS), AIDS, ARC(AIDS related complex), pneumonia, herpes virus; myalgias due toinfection; influenza; endotoxic shock; toxic shock syndrome;’ autoimmunedisease, graft vs. host reaction and allograft rejections; treatment ofbone resorption diseases, osteoporosis; multiple sclerosis; disorders ofthe female reproductive system, endometriosis; hemaginomas, infantilehemagionmas, angiofibroma of the nasopharynx, avascular necrosis ofbone; benign and malignant tumors/neoplasia, cancer, colorectal cancer,brain cancer, bone cancer, epithelial call-derived neoplasia (epithelialcarcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinalcancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer,stomach cancer, colon cancer, liver cancer, bladder cancer, pancreascancer, ovarian cancer, cervical cancer, lung cancer, breast cancer,skin cancer, squamus cell and/or basal cell cancers, prostate cancer,renal cell carcinoma, and other known cancers that affect epithelialcells throughout the body; leukemia; lymphoma; systemic lupuserthrematosis (SLE); angiogenesis including neoplasia; metastasis;central nervous system disorders, central nervous system disordershaving an inflammatory or apoptotic component, Alzheimer's disease,Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis, spinal cord injury, and peripheral neuropathy.
 52. A methodof treating a p38 kinase or TNF-alpha mediated disorder comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim 1 and at least onepharmaceutically acceptable carrier, adjuvant, solvent or excipient. 53.A compound according to claim 27 or claim 38, which is1-benzyl-4-(benzyloxy)-3-bromopyridin-2(1Hl)-one;3-bromo-1-(4-fluorobenzyl)-4-((4-fluorobenzyl)oxy]pyridin-2(1H)-one;3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-dimethylphenyl)-6-methylpyridin-2(11H)-one;4-(benzyloxy)_(n)-3-bromo-1-(4-fluorobenzyl)pyridin-2(1H)-one;3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H)-one;3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;4-bromo-2-(2,6-dichlorophenyl)-5-[(2,4-difluorobenzyl)oxy]pyridazin-3(2H)-one;3-bromo-1-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;3-bromo-1-(3-fluorobenzyl)-4-[(3-methylbenzyl)oxy]pyridin-2(1H)-one;3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one;1-benzyl-4-(benzyloxy)-3-bromo-6-methylpyridin-2(1H)-one;3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-methoxy-6-methylphenyl)-6-methylpyridin-2(1H)-one;3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-fluorobenzyl)pyridin-2(1H)-one;3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;3-bromo-1-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(11H)-one;4-(benzyloxy)-3-bromo-1-(4-methylbenzyl)pyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-(4-chlorobenzyl)pyridin-2(1H)-one;3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-methoxybenzyl)pyridin-2(1H)-one; 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoicacid; 4-(benzyloxy)-3-bromo-1-(2-fluorobenzyl)pyridin-2 (1H)-one;3-bromo-1-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-[4-(methylthio)benzyl]pyridin-2(1H)-one;1-benzyl-4-(benzyloxy)-3-chloropyridin-2(1H)-one;4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}-N′-hydroxybenzenecarboximidamide; methyl4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1 (2H) -yl]methyl}benzoate;3-bromo-4-[(3-chlorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H) -one;3-bromo-1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;4-(benzyloxy)-3-bromo-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one;3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-(4-bromobenzyl)pyridin-2 (1H)-one;4-{[3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-2(1H)-one;4-bromo-2-(2,6-dichlorophenyl)-5-{[2-(hydroxymethyl)benzyl]oxy}pyridazin-3(21)-one;3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;3-bromo-1-(2,4-difluorobenzyl)-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-2-ylmethyl)pyridin-2(1H)-one;or a pharmaceutically acceptable salt thereof.
 54. A compound accordingto any one of the preceding claims which is2-benzyl-5-(2,6-dichlorophenyl)-3,4-dimethyl-1,5-dihydro-6H-pyrrolo[3,2-c]pyridin-6-one;3-bromo-4-[(4-chlorobenzyl)oxy]-1-(4-fluorobenzyl)pyridin-2(1H)-one;1-benzyl-3-bromo-4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one;3-bromo-1-(4-chlorobenzyl)-4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one;3-bromo-4-[(4-chlorobenzyl)oxy]-1-[2-(phenylthio)ethyl]pyridin-2(1H)-one;3-bromo-4-[(4-chlorobenzyl)oxy]-1-(2-phenylethyl)pyridin-2(1H)-one;3-bromo-4-hydroxy-1-(4-hydroxybenzyl)pyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-(piperidin-3-ylmethyl)pyridin-2(1H)-onehydrochloride; 3-bromo-1-(4-methoxybenzyl)-4-phenoxypyridin-2(111)-one;1-benzyl-2-oxo-4-phenoxy-1,2-dihydropyridine-3-carbaldehyde;3-bromo-4-[(4-chlorobenzyl)oxy]-1-(4-methoxybenzyl)pyridin-2(1H)-one;3-bromo-4-[(4-fluorobenzyl)oxy]-1-(3-phenylpropyl)pyridin-2(1H)-one,4-(benzyloxy)-1-[4-(benzyloxy)benzyl]-3-bromopyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-[2-(trifluoromethyl)benzyl]pyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-[3-(trifluoromethyl)benzyl]pyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-(piperidin-4-ylmethyl)pyridin-2(1H)-onehydrochloride; 1-benzyl-4-(benzylthio)-3-bromopyridin-2(1H)-one;1-benzyl-3-bromo-4-{[2-(trifluoromethyl)benzyl]oxy}pyridin-2(1H)-one;1-benzyl-4-[(2,6-dichlorobenzyl)oxy]pyridin-2(1H)-one;1-benzyl-4-(benzyloxy)-3-(hydroxymethyl)pyridin-2(1H)-one;1-benzyl-3-bromo-4-[(2,6-dichlorobenzyl)oxy]pyridin-2(1H)-one;1-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;1-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;1-benzyl-3-bromo-4-[(2-chlorobenzyl)oxy]pyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-ethylpyridin-2(1H)-one;4-(benzyloxy)-1-(4-bromobenzyl)pyridin-2(1H)-one;3-bromo-1-(4-methylbenzyl)-4-[(4-methylbenzyl)oxy]pyridin-2(1H)-one;methyl 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl }benzoate;4-(benzyloxy)-3-bromo-1-(2-thien-3-ylethyl)pyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-(2-thien-2-ylethyl)pyridin-2(1H)-one;1-benzyl-4-[(3-chlorobenzyl)oxy]pyridin-2(1H)-one;3-bromo-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one;4-(benzyloxy)-1-(2-fluorobenzyl)pyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-methylpyridin-2(1H)-one hydrobromide;4-(benzyloxy)-3-bromo-1-methylpyridin-2(1H)-one;3-bromo-1-(3-chlorobenzyl)-4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one;3-bromo-1-(3-chlorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;4-(benzyloxy)-1-(4-chlorobenzyl)pyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-[4-(trifluoromethoxy)benzyl]pyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-(4-tert-butylbenzyl)pyridin-2(1H)-one;1-benzyl-4-(benzyloxy)-6-methylpyridin-2(1H)-one;1-benzyl-4-(benzyloxy)-3,5-dibromo-6-methylpyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-[4-(trifluoromethyl)benzyl]pyridin-2(1H)-one;1-benzyl-4-[(2-chlorobenzyl)oxy]pyridin-2(1H)-one;1-(2-bromobenzyl)-3-[(2-bromobenzyl)oxy]pyridin-2(1H)-one; methyl5-chloro-1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridine-3-carboxylate;3-benzyl-4-hydroxy-1-(2-phenylethyl)pyridin-2(1H)-one;5-bromo-1-(2-chloro-6-fluorobenzyl)-3-methylpyridin-2(1H)-one;1-(2-bromobenzyl)-3-[(2-bromobenzyl)oxy]pyridin-2(1H)-one;1-benzyl-4-(benzyloxy)pyridin-2(1H)-one;1-benzyl-4-(benzyloxy)-3-bromopyridin-2(1H)-one;1-benzyl-4-(benzyloxy)-2-oxo-1,2-dihydropyridine-3-carbaldehyde;1-benzyl-4-chloro-2-oxo-1,2-dihydropyridine-3-carbaldehyde;1-benzyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carbaldehyde;1-benzyl-4-(benzyloxy)-3-methylpyridin-2(1H)-one;4-(benzyloxy)-1-(4-fluorobenzyl)pyridin-2(1H)-one;1-benzyl-4-(benzyloxy)-3,5-dibromopyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-[4-(methylthio)benzyl]pyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-(4-fluorobenzyl)pyridin-2(1H)-one;1-benzyl-4-(benzyloxy)-3-chloropyridin-2(1H)-one;3-bromo-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;5-benzyl-1,2,7-trimethyl-3-(phenylthio)-1,5-dihydro-6H-pyrrolo[3,2-c]pyridin-6-one;1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl methyl(phenyl)carbamate;1-benzyl-3-bromo-4-(2-phenylethyl)pyridin-2(1H)-one;1-benzyl-3-bromo-4-(3-phenylpropyl)pyridin-2(1H)-one;1-benzyl-3-methyl-4-(2-phenylethyl)pyridin-2(1H)-one;1-benzyl-3-methyl-4-(3-phenylpropyl)pyridin-2(1H)-one;1-benzyl-4-(benzylthio)-3-methylpyridin-2(1H)-one;1-benzyl-4-(benzylthio)-3-bromopyridin-2(1H)-one; (product)1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methanesulfonate;3-acetyl-4-hydroxy-6-methyl-1-[choro]phenylpyridin-2(1H)-one;6-(benzyloxy)-1-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile;3-benzoyl-6-(benzyloxy)-1-methylpyridin-2(1H)-one;3-benzyl-6-(benzyloxy)-1-methylpyridin-2(1H)-one;1-benzyl-4-hydroxypyridin-2(1H)-one;1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methanesulfonate;1-benzyl-4-(benzylthio)pyridin-2(1H)-one1-benzyl-4-(benzylthio)-3-bromopyridin-2(1H)-one;1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methanesulfonate;4-amino-1-benzylpyridin-2(1H)-one;1-benzyl-4-(benzyloxy)pyridin-2(1H)-one;1-benzyl-4-hydroxypyridin-2(1H)-one;1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methyl(phenyl)carbamate; or apharmaceutically acceptable thereof.
 55. A compound according to any oneof the preceding claims that is4-(benzyloxy)-1-(4-methylbenzyl)pyridin-2(1H)-one;4-(benzyloxy)-3-bromopyridin-2(1H)-one; methyl4-{[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]methyl} benzoate;methyl-4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl} benzoate;4-{[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]methyl} benzonitrile;4-(benzyloxy)-1-(4-tert-butylbenzyl)pyridin-2(1H)-one;4-(benzyloxy)-1-[4-(trifluoromethyl)benzyllpyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-[4-(trifluoromethyl) benzyl]pyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-[3-(trifluoromethyl) benzyl]pyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-[2-(trifluoromethyl) benzyl]pyridin-2(1H)-one;4-(benzyloxy)-1-[4-(trifluoromethoxy)benzyl1pyridin-2(1H)-one;4-(benzyloxy)-3-bromo-1-[4-(trifluoromethoxy) benzyl]pyridin-2(1H)-one;1-benzyl-4-hydroxy-6-methylpyridin-2(1H)-one;1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl 4-bromobenzenesulfonate;1-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl 4-bromobenzenesulfonate;1-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;1-Benzyl-4-[2,6-(dichlorobenzyl)oxy]pyridin-2(1H)-one;4-[(2,6-dichlororbenzyl)oxy]pyridine-1-oxide;4-[(2,6-dichlorobenzyl)oxy]pyridine 1-oxide;1-Benzyl-3-bromo-4-[2,6-(dichlorobenzyl)oxy]pyridin-2(1H)-one;1-Benzyl-3-bromo-4-[(4-methylbenzyl)oxy]pyridin-2(1H)-one;1-Benzyl-4-[benzylthio]-3-bromopyridin-2(1H)-one;1-benzyl-4-(benzyloxy)-3-iodopyridin-2(1H)-one;1-benzyl-4-(benzyloxy)-3-vinylpyridin-2(1H)-one;1-benzyl-4-(benzyloxy)-3-ethylpyridin-2(1H)-one;3-acetyl-4-(benzyloxy)-1-(2-chlorophenyl)-6-methylpyridin-2(1H)-one;3-acetyl-1-(2-chlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one;1-benzyl-3-bromo-4-hydroxypyridin-2(1H)-one;1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate;1-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(1H)-one;3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(2-phenylethyl)pyridin-2(1H)-one;1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one;3-bromo-1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one;3-bromo-1-(3-fluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate;3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(phenylethynyl)pyridin-2(1H)-one;3-acetyl-1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one;1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H) one;4-(benzyloxy)-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one;3-bromo-1-(3-fluorobenzyl)-4-(2-phenylethyl)pyridin-2(1H)-one;3-bromo₇1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one;3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate;3-bromo-1-(3-fluorobenzyl)-4-(phenylethynyl)pyridin-2(1H)-one;4-(benzyloxy)-3-ethynyl-1-(3-fluorobenzyl)pyridin-2(1H)-one;4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one;4-(benzyloxy)-1-(3-fluorobenzyl)-3-[(trimethylsilyl)ethynyl]pyridin-2(1H)-one;4-(benzylamino)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one;1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one;4-(benzylamino)-1-(3-fluorobenzyl)pyridin-2(1H)-one; or apharmaceutically acceptable salt thereof.
 56. A compound according toany one of the preceding claims which is3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-fluorobenzyl)pyridin-2(1H)-one;3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;3-bromo-1-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-methoxybenzyl)pyridin-2(1H)-one;3-bromo-1-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H) -one;3-bromo-4-[(3-chlorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H)-one;3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;3-bromo-1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;4-{[3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-2(1H)-one;3-bromo-4-((4-fluorobenzyl)oxy]-(pyridin-3-ylmethyl)pyridin-2(1H)-one;3-bromo-1-(2,4-difluorobenzyl)-4-1(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-2-ylmethyl)pyridin-2(1H)-one;3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H)-one;3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;3-bromo-1-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;3-bromo-1-(3-fluorobenzyl)-4-[(3-methylbenzyl)oxy]piperidin-2-one;3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-methoxy-6-methylphenyl)-6-methylpyridin-2(1H)-one;or a pharmaceutically acceptable salt thereof.